Hair, Skin And Nails [Discontinued] by The Vitamin Shoppe

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral betaine hydrochloride for allergic rhinitis, there is insufficient reliable information about the clinical use of betaine hydrochloride for this purpose.
• Asthma. Although there has been interest in using oral betaine hydrochloride for asthma, there is insufficient reliable information about the clinical use of betaine hydrochloride for this purpose.
• Atherosclerosis. Although there has been interest in using oral betaine hydrochloride for atherosclerosis, there is insufficient reliable information about the clinical use of betaine hydrochloride for this purpose.
• Diarrhea. Although there has been interest in using oral betaine hydrochloride for diarrhea, there is insufficient reliable information about the clinical use of betaine hydrochloride for this purpose.
• Dyspepsia. Although there has been interest in using oral betaine hydrochloride for indigestion caused by hypochlorhydria, there is insufficient reliable information about the clinical use of betaine hydrochloride for this purpose.
• Food allergies. Although there has been interest in using oral betaine hydrochloride for food allergies, there is insufficient reliable information about the clinical use of betaine hydrochloride for this purpose.
• Gallbladder disease. Although there has been interest in using oral betaine hydrochloride for gallbladder disease, there is insufficient reliable information about the clinical use of betaine hydrochloride for this purpose.
• Hyperhomocysteinemia. Although there has been interest in using oral betaine hydrochloride for hyperhomocysteinemia, there is insufficient reliable information about the clinical use of betaine hydrochloride for this purpose.
• Hypothyroidism. Although there has been interest in using oral betaine hydrochloride for hypothyroidism, there is insufficient reliable information about the clinical use of betaine hydrochloride for this purpose.
• Rheumatoid arthritis (RA). Although there has been interest in using oral betaine hydrochloride for RA, there is insufficient reliable information about the clinical use of betaine hydrochloride for this purpose. More evidence is needed to rate betaine hydrochloride for these uses.

(Read more about BETAINE HYDROCHLORIDE)

LIKELY EFFECTIVE

• Biotin deficiency. Oral and injectable biotin prevents and treats biotin deficiency. Details: Biotin up to 10 mg daily has been used to treat and prevent biotin deficiency. Injections of biotin 150 mcg daily for 3-5 days have been used in adults. Biotin deficiency might occur due to different etiologies such as inherited biotinidase deficiency, malnutrition, chronic use of anticonvulsants, pregnancy, and excessive and chronic raw egg consumption (6243,19347). A very small study in newborns aged 1-6 months shows that adding biotin to infant formula safely improves biotin status in formula-fed infants (111365). The validity of these findings is limited by a lack of blinding, no randomization, and the small sample size.

POSSIBLY INEFFECTIVE

• Multiple sclerosis (MS). In spite of contrary reports, high-dose biotin (300 mg daily) does not reduce disability in patients with progressive MS. It also does not seem to be linked to an increased risk for relapse. Details: Although most earlier research suggested benefit, the highest quality evidence shows that high-dose biotin does not improve outcomes in progressive MS (95662,102963,102966,104011). A large multi-centered randomized clinical trial (SPI2) in patients with progressive MS and high disability shows that taking biotin 100 mg three times daily for 15 months does not improve disability, as measured on the expanded disability status scale (EDSS), or 25-foot walking time, when compared with placebo. The SPI2 clinical trial also did not find that biotin increases the rate of relapse (104011), a concern raised in one observational study of high-dose biotin (104000). Also, a large observational study of adults with progressive MS failed to identity an increase in annualized relapse rates in patients that reported taking biotin when compared with controls (105716). Other observational research has also found no effect on the relapse risk (102963,102964). There is some speculation that any increased rate of relapse identified in some high-dose biotin cohorts might be due to detection bias or reduced compliance with disease-modifying therapies.
• Seborrheic dermatitis. Oral biotin doesn't seem to improve seborrheic dermatitis of infancy. Details: A clinical trial in infants with seborrheic dermatitis shows that biotin given by mouth does not improve symptoms when compared with placebo (8469).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alopecia areata. It is unclear if oral biotin is beneficial for alopecia areata. Details: A small clinical study in healthy adults with alopecia areata shows that weekly injections of intramuscular biotin 5 mg/1 mL and dexpanthenol 250 mg/2 mL for 6 weeks reduces hair fall count and transiently increases hair density compared with baseline (111366). The validity of these findings is limited by a lack of a placebo control group, small sample size, and short duration of treatment. It is unclear if the effects are due to biotin, dexpanthenol, or the combination. Another small clinical study in 9-year-old children with alopecia areata shows that taking biotin 20 mg with zinc aspartate 100 mg orally along with topical application of clobetasol propionate 0.025% daily for one year promotes hair regrowth in 33% of children, compared with 0% in the group receiving the steroid deflazacort (6932). It is unclear if these effects are due to biotin, zinc, topical clobetasol, or the combination.
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). Although there is interest in using oral biotin for ALS, there is insufficient reliable information about the clinical effects of biotin for this condition.
• Biotin-thiamine-responsive basal ganglia disease. Adding oral biotin to oral thiamine does not seem to improve most symptoms associated with this condition, although it may slightly speed recovery from acute crisis in children. Details: A small case series in children ages 1-12 years with biotin-thiamine-responsive basal ganglia disease has found that adding biotin 5 mg/kg daily to thiamine 40 mg/kg daily for 30 months is not associated with additional symptomatic improvement in encephalopathy, seizures, dystonia, or other neurologic sequelae when compared with taking only thiamine. However, taking biotin with thiamine is associated with a 1-day reduction in recovery from acute crisis when compared with thiamine alone (95661).
• Brittle nails. Low quality clinical studies suggest that oral biotin might improve nail thickness and prevent the splitting of brittle nails. Details: Some small, low quality clinical studies in people with brittle nails shows that taking biotin 2.5 mg orally daily for 1.5 to 15 months increases nail thickness and decreases the splitting of fingernails and toenails in some people when compared with baseline (171,35593). The validity of these findings is limited by the small study sizes and the lack of a comparator group.
• Depression. Although there is interest in using oral biotin for mild depression, there is insufficient reliable information about the clinical effects of biotin for this condition.
• Diabetes. It is unclear if oral biotin is beneficial for type 2 diabetes. Details: A meta-analysis of randomized controlled trials shows that taking biotin 1.5-15 mg orally daily for 1-3 months does not improve fasting blood glucose or serum insulin levels when compared with placebo. However, the validity of these results is limited by inclusion of subjects with and without diabetes (110044). A very small study in adults with type 2 diabetes also shows that taking biotin 5 mg three times daily for 28 days does not affect glucose or insulin levels when compared to baseline (11579). Biotin has also been studied in combination with other ingredients. Preliminary clinical research shows that a taking a specific supplement containing a combination of biotin 2 mg and chromium picolinate 600 mcg (Diachrome, Nutrition 21) can lower blood glucose and glycated hemoglobin levels in patients with type 2 diabetes who are poorly controlled on oral hypoglycemic drugs (12385,12390,15169). It is unclear if these effects are due to biotin, chromium, or the combination.
• Diabetic neuropathy. Although there is interest in using oral and intramuscular biotin for diabetic neuropathy, there is insufficient reliable information about the clinical effects of biotin for this condition.
• Muscle cramps. It is unclear if biotin is beneficial for improving muscle cramps in patients undergoing hemodialysis. Details: Patients undergoing hemodialysis are prone to muscle cramps. A small clinical study in patients with hemodialysis-related muscle cramps shows that taking biotin 1 mg in the morning daily for at least one week prevents and reduces severity of muscle cramps when compared to baseline. Cessation of biotin led to recurrence of cramps, and restarting oral biotin led to resolution of cramps during hemodialysis (89475). The validity of these findings is limited by the lack of comparator group. More evidence is needed to rate biotin for these uses.

(Read more about BIOTIN)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral bromelain for allergic rhinitis, there is insufficient reliable information about the clinical effects of bromelain for this condition.
• Aromatase inhibitor-induced arthralgia. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with aromatase inhibitor-induced arthralgia shows that taking a specific combination product (Opera, Gam Farma), providing bromelain 20 mg, alpha-lipoic acid 240 mg, Boswellia serrata 40 mg, and methylsulfonylmethane 200 mg, daily for 6 months reduces arthralgia symptoms when compared to baseline (109570). The validity of these findings is limited by a lack of placebo control group. Further, it is unclear if these findings are due to bromelain, other ingredients, or the combination.
• Burns. Preliminary clinical research shows that topical bromelain is beneficial for burn debridement. However, it is unclear if topical bromelain is beneficial for scar prevention. Details: Preliminary clinical research and chart reviews show that gels formulated with proteolytic enzymes derived from bromelain (Debridase or NexoBrid, MediWound Ltd.) applied under an occlusive dressing for 4 hours help debride burns, including chemical and electrical burns, in children and adults (18275,91113,103297,108149). Further, a meta-analysis of up to 5 lower- to moderate-quality clinical and observational studies in children and adults with deep burns shows that enzymatic debridement with a specific bromelain based proteolytic enzyme gel applied once or twice for a 4 hour period reduces eschar time by approximately 7 days and reduces the relative risk of surgical excision, and autografts by 83%, and 60%, respectively, when compared with standard of care (e.g., surgical and non-surgical procedures) (115870). The validity of these results is limited by significant heterogeneity across clinical studies, including differences in the location of burns and extent of total body surface area affected.
• Cancer. Although there has been interest in using oral bromelain for cancer, there is insufficient reliable information about the clinical effects of bromelain for this condition.
• Chemotherapy-induced peripheral neuropathy. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with chemotherapy-induced peripheral neuropathy shows that taking a specific product (Opera, Gamfarma s.r.l.) containing bromelain 20 mg, alpha-lipoic acid 240 mg, methylsulfonylmethane (MSM) 200 mg, and boswellia 40 mg daily for 12 weeks reduces overall pain when compared with baseline (96449). The validity of these findings is limited by the lack of a control group. Additionally, it is not clear if benefit is due to alpha-lipoic acid, the other ingredients, or the combination.
• Chronic venous insufficiency. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: An observational study in adults with chronic venous insufficiency using compression stockings shows that taking a specific supplement containing bromelain dry extract 50-200 mg, Baikal skullcap, and horse chestnut (Lenidase, Enfarma), dose adjusted based on severity, daily for up to 90 days, improves severity of lower extremity symptoms (e.g., inflammation, pain, varicose veins, vessel induration) when compared with the use of compression stockings alone (115869). It is unclear if these benefits are due to bromelain, the other ingredients, or the combination.
• Diabetes. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small observational study in patients with a family history of type 1 diabetes found that taking a specific product (Mucos Pharma) containing bromelain 90 mg. rutin 100 mg, and trypsin 48 mg daily for 24 months is not associated with reduced incidence of type 1 diabetes at 8 years (99472).
• Diabetic foot ulcers. Although there has been interest in using topical bromelain for diabetic foot ulcers, there is insufficient reliable information about the clinical effects of bromelain for this condition.
• Exercise-induced muscle soreness. It is unclear if oral bromelain is beneficial for preventing exercise-induced muscle soreness. Details: One small clinical study shows that taking bromelain 300 mg three times daily, immediately following an intense exercise regimen, does not reduce delayed onset muscle soreness and has no effect on pain, flexibility, or skeletal weakness when compared with either ibuprofen 400 mg three times daily or placebo (10622). However, a small clinical study shows that taking a combination protease tablet containing bromelain 50 mg, trypsin 75 mg, papain 50 mg, amylase 10 mg, lipase 10 mg, lysosome 10 mg, and chymotrypsin 2 mg, four times in one day before downhill running, can improve recovery of contractile muscle function and decrease muscle soreness when compared with placebo (67838). It is unclear if these effects are due to bromelain, other ingredients, or the combination.
• Exercise-induced respiratory infections. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in non-elite male runners shows that taking a combination product (Wobenzym Plus, Mucos Pharma) providing bromelain 540-1080 mg, rutin 600-1200 mg, and trypsin 288-576 mg daily for 3 weeks, starting one week before a marathon, does not reduce the risk of a post-race respiratory tract infection when compared with placebo (96766).
• Kidney stones (nephrolithiasis). It is unclear if oral bromelain is beneficial for kidney stone expulsion. Details: Observational research in patients with 4-10 mm kidney stones found that adding bromelain to tamsulosin is associated with a 12% increased rate of spontaneous stone expulsion when compared to tamsulosin alone (100752).
• Knee pain. It is unclear if oral bromelain is beneficial for knee pain. Details: Preliminary clinical research shows that taking bromelain (Bromelin, Lichtwer Pharma Ltd.) orally for 30 days can reduce mild, acute (duration of less than 3 months) knee pain in otherwise healthy patients when compared to baseline. A daily dose of 400 mg seems to be more effective than 200 mg daily for relieving pain, stiffness, and physical function of the knee, with reductions in symptom scores of 59% and 41%, respectively (11457).
• Lymphedema. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some clinical research in patients who have undergone a mastectomy shows that taking a specific combination product containing bromelain, rutin, pancreatin, papain, trypsin, and chymotrypsin (Wobenzym N, Mucos Pharma) daily for 7 weeks reduces arm swelling associated with lymphedema when compared with diuretics (24560). Other preliminary clinical research in patients with primary or secondary lymphedema of the upper or lower limbs shows that taking a different combination product containing bromelain 100 mg, rutin 300 mg, and sweet clover 100 mg daily for 6 months decreases pitting, limb volume, pain, and quality of life when compared to baseline (103298). The validity of these results is limited by the lack of a control group. Additionally, it is unclear if these findings are due to bromelain, other ingredients, or the combination.
• Multiple sclerosis (MS). Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A preliminary clinical study in patients with relapsing-remitting MS shows that taking an enzyme combination containing bromelain 90 mg, rutin 100 mg, and trypsin 48 mg per tablet for at least 3 months does not affect the progression of disability, relapse rate, or central nervous system lesions when compared with placebo (99468). The validity of these results is limited by the short duration of treatment.
• Ocular floaters. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in patients with spontaneous symptomatic vitreous opacities (ocular floaters) shows that taking oral mixed fruit enzyme capsules containing bromelain 190 mg, papain, and ficin once, twice, or three times daily for 3 months eliminates floaters in 55%, 63%, and 70% of patients, respectively, when compared with an elimination rate of 5% with vitamin C as a control. Additionally, patients with vitreous hemorrhage-induced symptomatic vitreous opacities taking the mixed fruit enzyme capsules 3 times daily for 3 months reduced intraocular blood by 56% and improved visual acuity, but these effects were not found for lower doses and shorter durations when compared with a control (111650). It is unclear if these effects are due to bromelain, other ingredients, or the combination.
• Osteoarthritis. It is unclear if oral bromelain is beneficial for osteoarthritis. Details: A small clinical trial shows that taking bromelain 800 mg daily for 12 weeks as an adjunctive treatment for moderate to severe knee osteoarthritis is no more effective than placebo for improving symptom scores (18274). Other preliminary clinical research shows that taking bromelain 500 mg daily for 4 weeks for mild to moderate knee osteoarthritis is less effective than diclofenac 100 mg daily for improving quality of life, joint pain, and joint function (96216). However, preliminary clinical research shows that oral combination products containing bromelain can reduce pain and improve function in knee osteoarthritis (6252,91104,91106,99467,99477,103299). Bromelain 180 mg has been used in combination with trypsin 144 mg and rutin 200 mg (Phlogenzym, Mucos Pharma GMBH; Wobenzym, Mucos Pharma GmbH) three times daily for 3-12 weeks, with effects comparable to diclofenac, usually taken as 50 mg three times daily for one week, then twice daily thereafter. This product also reduces the need for rescue analgesics by 95% when compared with placebo (6252,91104,99467,99477). Other studies have used a specific combination supplement (AINAT, Laboratoire de Rhumatologie Appliquée) containing Devil's claw 600 mg, turmeric 400 mg, and bromelain 300 mg, taken 2-3 times daily for 2-8 weeks (91106) or a combination of bromelain 250 mg and papain 250 mg (Nature's Life Bromelain & Papain, NutraMarks, Inc.) twice daily, plus aceclofenac 100 mg twice daily for 6 weeks (103299).
• Pain (acute). It is unclear if oral bromelain is beneficial for acute pain. Details: A meta-analysis of 9 small clinical studies in patients experiencing acute pain due to various etiologies shows that taking bromelain slightly improves subjective pain scores and allows patients to open their mouth wider after oral operations when compared with a control (113513).
• Parturition. Although there has been interest in using oral bromelain for shortening the duration of labor, there is insufficient reliable information about the clinical effects of bromelain for this purpose.
• Periodontitis. It is unclear if oral bromelain is beneficial for periodontitis. Details: A very small clinical study in adults with periodontitis shows that taking bromelain 500 mg (Anaheal) twice daily for one week after undergoing pocket elimination surgery reduces bleeding on probing but does not improve gingival index, plaque index, or probing pocket depth when compared with placebo when assessed five weeks after surgery (111691). The validity of these effects is limited by a very small sample size and inadequate statistical power.
• Pityriasis lichenoides chronica (PLC). It is unclear if oral bromelain is beneficial for PLC. Details: A case series suggests that taking bromelain 40 mg orally three times daily for one month, then twice daily for a second month, then once daily for a third month, helps treat episodes of PLC when compared to baseline (18280).
• Postoperative pain. While evidence is mixed, some small clinical studies suggest that oral bromelain reduces postoperative pain aftersome oral surgeries. Details: Meta-analyses and clinical research in a small number of patients undergoing wisdom tooth extraction shows that bromelain modestly reduces pain for up to 8 days when compared with control (91109,91110,100750,100751). In contrast, several other small clinical studies show that taking bromelain does not reduce pain after wisdom tooth extraction when compared with placebo (91107,96214,96215). These studies might not have been sufficiently powered to detect a smaller effect. Meta-analyses also suggest that bromelain does not appear to have a significant effect on postoperative swelling or trismus (100750,100751). Additionally, multiple clinical studies in patients undergoing oral procedures, including crown lengthening or root canal surgery, shows that bromelain 160-1500 mg, taken in 2-4 divided doses daily for up to 6 days, reduces dental pain, swelling, and trismus similarly to taking non-steroidal anti-inflammatories (e.g., ketoprofen, diclofenac sodium, aceclofenac, and ibuprofen) (91109,91110,110546,113898,115871,110546). Bromelain, in combination with other ingredients, has also been evaluated for reducing pain after surgery. Several clinical trials in adults undergoing a variety of surgery types, including facial trauma, hernioplasty, oral surgery, and shoulder surgery, show that taking specific combination products (Siben, Brovas, Tenosan) containing bromelain and other ingredients (e.g., freeze-dried pineapple, methylsulfonylmethane, Boswellia serrata) daily for 1 week to 3 months reduces postoperative pain (115868,19322,114687,115304). However, clinical significance is unclear. Additionally, it is unclear if the effect is due to bromelain, other ingredients, or the combination.
• Postoperative swelling. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small preliminary clinical study in patients undergoing surgery of the jaw shows that taking an enzyme combination of bromelain 180 mg, rutin 200 mg, and trypsin 96 mg twice daily for 5 days in addition to standard treatment reduces soft-tissue thickness (indicating the amount of swelling) at most of the nine assessed facial points when compared to control (99476).
• Rhinosinusitis. It is unclear if oral bromelain is beneficial for rhinosinusitis. Details: Several small clinical trials show that short-term and long-term use of bromelain reduces symptoms of acute and chronic sinusitis, especially nasal mucosal inflammation and edema (18276,18277,18278,18279,91105). The trials used bromelain 40 mg orally (usually the product Ananase) four times daily for six days as an adjunct to antibiotics (18276,18278,18279) or 6 bromelain tablets each containing enzymes of 500 International Pharmaceutical Federation (FIP) units for 12 weeks (91105). Bromelain is usually taken in combination with decongestants, antihistamines, and/or antibiotics. However, the studies have a number of methodological problems, and results are inconsistent. Bromelain has also been evaluated as part of a combination product. A small study in patients over 12 years old with chronic sinusitis shows that taking a combination product containing bromelain 200 mg, Boswellia serrata, black currant, and vitamin D (Flogostop Forte, Humana Italia S.p.A) 1-2 times daily for 15-30 days as an adjunctive therapy to inhaled corticosteroids modulates hyperemia of the mucosa, rhinorrhea, and local inflammation when compared with inhaled corticosteroids alone and baseline (111501). It is unclear if these findings are due to bromelain, other ingredients, or the combination.
• Sprains. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A preliminary clinical study in patients with a sprained ankle shows that taking a specific enzyme combination (Phlogenzym, Mucos Pharma) containing bromelain 90 mg, trypsin 48 mg, and rutin 100 mg, or taking different combinations of the individual enzymes three times daily for 10 days, is no more effective for relieving pain than placebo (99473).
• Tendinopathy. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with Achilles tendon insertional tendinopathy shows that taking two sachets of a specific supplement (Tenosan, Agave, Prato, Italy) containing a total of bromelain 100 mg, arginine-L-alpha-ketoglutarate 1000 mg, methylsulfonylmethane (MSM) 1100 mg, hydrolyzed collagen type I 600 mg, vitamin C 120 mg, and Vinitrox 25 mg orally for 60 days improves function and pain when compared with placebo (19321).
• Urinary tract infections (UTIs). Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial shows that a combination of bromelain 50 mg and trypsin 1 mg (Kimotab, Mochida Pharmaceutical), taken in a dose of 8 tablets daily for 2 days, does not improve subjective symptoms of UTIs when compared with placebo (18282).
• Venous leg ulcers. Although there has been interest in using topical bromelain for venous leg ulcers, there is insufficient reliable information about the clinical effects of bromelain for this condition.
• Wound healing. It is unclear if enzymatic debridement with bromelain improves the healing of various types of chronic wounds. Details: A meta-analysis of 12 small clinical studies shows that topical bromelain reduces time to complete debridement by around 6 days but has no effect on time to healing when compared with a control (113513). However, the validity of these effects is limited by significant publication bias and a small number of studies per outcome. One small clinical study, included in the analysis above, of patients with chronic wounds related to diabetes, surgery, trauma, or venous insufficiency shows that use of bromelain-based enzymatic debridement (EscharEx, MediWound Ltd), administered as up to ten daily applications of 4 hours each, increases the incidence of complete debridement over the next 6 months to 55% of patients, compared with only 29% of those using the bromelain-free gel. However, there was no difference in changes in wound area, non-viable tissue area, or the incidence or time to complete wound closure (108148). More evidence is needed to rate bromelain for these uses.

(Read more about BROMELAIN)

EFFECTIVE

• Dyspepsia. Oral calcium carbonate is approved by the US Food and Drug Administration (FDA) as an antacid. Details: Taking calcium carbonate orally as an antacid is effective for treating dyspepsia (1843). Calcium carbonate has FDA approval as an antacid.
• Hyperkalemia. Intravenous calcium gluconate is approved by the US Food and Drug Administration (FDA) for preventing hyperkalemia-induced cardiac abnormalities. Details: Administering calcium gluconate intravenously can reverse electrocardiographic changes and arrhythmias induced by hyperkalemia (12946). Intravenous calcium gluconate is FDA-approved for preventing hyperkalemia-induced cardiac abnormalities.
• Hypocalcemia. Oral calcium treats and prevents hypocalcemia. Intravenous calcium is used to treat severe hypocalcemia. Details: Taking calcium orally is effective for treating and preventing hypocalcemia. Intravenous calcium gluconate, acetate, gluceptate, or chloride is effective for severe hypocalcemia or hypocalcemic tetany (12928).
• Kidney failure. Oral calcium carbonate or calcium acetate is used as a phosphate binder during kidney failure. Details: Taking calcium carbonate or calcium acetate orally is effective as a phosphate binder. Calcium acetate (PhosLo) appears to control hyperphosphatemia better than sevelamer (Renagel) (12943,12944,38990). Calcium citrate is not recommended for this purpose because it increases aluminum absorption and does not bind phosphate as efficiently as calcium acetate or calcium carbonate (21631). Some clinical research also shows that taking calcium orally reduces blood pressure in patients with kidney failure (975).

LIKELY EFFECTIVE

• Corticosteroid-induced osteoporosis. Oral calcium in combination with vitamin D prevents bone density loss that occurs during long-term treatment with corticosteroids. Details: Taking calcium in combination with vitamin D as adjunctive therapy seems to be effective for reducing bone mineral density loss in people using corticosteroids long-term (982,1046,1830,1831,1832,4462,4463,4464,4465,4466)(4467,12945,38493). One specific product used in clinical research is Oscal (Marion Merrel Dow Inc.), which contains elemental calcium 500 mg per tablet plus vitamin D 125 IU per tablet (982). Another product used is Oscal 250 + D (SmithKline Beecham Healthcare), which contains elemental calcium 250 mg and vitamin D 125 IU per tablet (1046).
• Hyperparathyroidism. Oral calcium reduces parathyroid hormone levels in patients with secondary hyperparathyroidism due to kidney failure. Details: Taking calcium orally reduces parathyroid hormone levels in patients with kidney failure and secondary hyperparathyroidism (1827,1828,1829,39174,39425). In elderly women, the combination of calcium and vitamin D reverses secondary hyperparathyroidism and reduces hip fracture risk (8818). Also, population research suggests increased calcium intake from the diet and supplements reduces the risk of primary hyperparathyroidism in women. Supplemental intakes of at least 500 mg/day and dietary intakes of approximately 1100 mg/day are considered to be protective (91353).
• Osteoporosis. Adequate calcium intake, from the diet and/or supplements, is recommended for the prevention and treatment of osteoporosis. Details: The Bone Health and Osteoporosis Foundation (BHOF) recommends ensuring adequate calcium intake in line with the recommended dietary allowance (RDA) by age, along with adequate vitamin D intake, for the prevention and treatment of osteoporosis in adults over 50 years of age. Supplementation can be used to augment dietary intake when adequate dietary intake is not feasible (109425). In the US and Canada, foods containing at least 200 mg calcium with less phosphorous content than calcium can be labelled with a health claim regarding the relationship between adequate calcium intake and a reduced risk for osteoporosis (11940,102148). However, calcium supplementation is not recommended specifically for the primary prevention of osteoporosis. The US Preventive Task Force (USPSTF) states that the current evidence is insufficient to assess the balance of benefits and harms of vitamin D and calcium supplementation, alone or in combination, for the primary prevention of fractures in community dwelling adults without osteoporosis (95695). Also, calcium supplements do not seem to be effective for preventing loss of bone mineral density (BMD) during lactation (988), in patients who have had bone marrow transplantation (1817), or in patients who have had renal transplantation (4823,38736,38871). Maximal bone growth occurs in the teenage years, and then BMD in females remains relatively constant until age 30-40. After age 40, bone loss typically occurs at rates of 0.5% to 1% per year. In males, this occurs several decades later. Bone loss is more pronounced if dietary calcium intake is below the RDA, which is the case for many Americans (2571,2578). One meta-analysis of randomized controlled trials in healthy children 7-14 years old shows that fortifying food with calcium 250-1000 mg daily for up to 24 months modestly improves femoral neck BMD, but not hip or spine BMD. However, the included trials did not supplement vitamin D (107232). During the 5 years immediately after menopause, calcium supplementation has very little effect on bone loss (2569,2570,2575,2576). The rapid loss of estrogen causes a high bone resorption rate, which increases serum calcium levels and therefore decreases intestinal absorption of calcium (2570). After this period, the typical rate of bone loss is 2% per year (2572,2576). Taking calcium 1000-1600 mg daily as carbonate, citrate, lactate gluconate, or citrate malate salt decreases this rate by 0.25% to 1% annually (977,979,981,2569,2571,2572,2575,2576,2578,6850)(38978,38980,39064). The greatest reductions (1% or more) are seen in the first 1-2 years of supplementation when bone remodeling foci can be filled (2569,2576). After this period, the differences in rate of loss between supplemented and non-supplemented females are closer to 0.25% per year (2569,2577). A meta-analysis of clinical evidence suggests that there is no additional benefit after 4 years (38980). Small clinical studies have found that continuous calcium supplementation at an average daily dose of 1050 mg, started after menopause and continued for 1.5-4 years, may reduce fracture rates by 26% when compared with no calcium supplementation. The largest of these studies was conducted in nursing home residents who also received daily vitamin D; the benefits of calcium, specifically, are unclear (39386). Some research also suggests that calcium and vitamin D improves primary prevention of osteoporotic fractures in some older individuals with osteoporosis, particularly the elderly and those who are no longer community dwelling (12930,38875,38849,39026,109471). However, not all research is positive. One large clinical trial in elderly adults with a low-trauma fracture show that taking calcium 1000 mg daily with or without vitamin D 800 IU daily for 2-7 years does not reduce the risk of a second fracture when compared with placebo (13073). Another clinical study shows that taking calcium 1000 mg daily plus vitamin D 800 IU daily does not prevent a second fracture in elderly patients, or prevent a first fracture in elderly patients with other risk factors such as low body weight (less than 58 kg, 127.6 pounds), smoking, family history of hip fracture, or fair or poor self-reported health (12929). Also, some exploratory research suggests that supplements may need to be continued indefinitely; in adults over 68 years of age, any effects of 2 years of calcium supplements on BMD appear to be lost within 2 years after discontinuing supplements (6853). Calcium has additive effects when used with other agents such as vitamin D, estrogens, or calcitonin. Whereas calcium alone generally reduces or prevents loss of BMD, combination with other agents can produce small increases in BMD ranging from 0.3% to 3.3% depending on the combination and dosages used (978,980,1836,2570,2571,2572,2576). However, one meta-analysis in healthy adults shows that fortifying foods with calcium 250-1000 mg daily, in conjunction with vitamin D supplementation, for up to 24 months does not improve BMD when compared with control (107232). The full potential of osteoporosis treatments cannot be realized without adequate calcium intake (2569,2570,2571,2572). Advise patients taking agents such as estrogens, calcitonin, bisphosphonates, or raloxifene (Evista) to ensure that their daily calcium intake meets the RDA. Use supplements if necessary. The usefulness of calcium in preventing osteoporosis in males is not as well-studied. Some observational research has found that calcium 870 mg daily is not associated with changes in BMD and bone loss in males (97201). However, clinical evidence suggests that taking calcium 1000 mg daily for 2 years might improve trabecular or cortical bone mass by 2% to 4% (980,8827,8873). Dietary supplementation with calcium and vitamin D seems to moderately reduce bone loss measured in the femoral neck, spine, and total body, and seems to reduce the incidence of nonvertebral fractures in older patients with osteopenia or low BMD (980).
• Premenstrual syndrome (PMS). Adequate calcium intake seems to prevent symptoms of PMS. Details: There seems to be a link between low dietary calcium intake and symptoms of PMS (2004,6847,39007). Taking calcium 1000-1336 mg daily seems to significantly reduce depressed mood, water retention, and pain, especially if daily calcium intake is inadequate (1822,1823,1824,2004,95821). Calcium carbonate 1200 mg daily seems to decrease PMS symptom scores by about 18% when compared with placebo (1822). Increasing dietary calcium intake is also associated with a decreased risk of developing PMS. Consuming an average of 1283 mg of calcium per day from foods is associated with about a 30% lower risk of developing PMS compared with consuming an average of 529 mg daily (13094); however, taking calcium supplements does not appear to be associated with the risk of developing PMS.

POSSIBLY EFFECTIVE

• Colorectal cancer. Oral calcium seems to be beneficial for preventing colorectal cancer, especially in those with adequate vitamin D levels and normal body mass index (BMI). Details: Population studies have found that increased intake of dietary or supplemental calcium is associated with a reduced risk of colorectal cancer and colorectal adenomas (1047,8820,12120,38951,98898,98899). Clinical trials and meta-analyses of clinical research also show that taking calcium supplements 1.2-2 grams daily for up to 4 years can reduce the risk of colorectal adenoma recurrence by up to 29% (970,12118,12950,15267,34596,38718,39042,95817). However, not all research has been positive. Some meta-analyses of clinical research or observational studies suggest that taking calcium does not reduce the risk of familial adenomatous polyposis or colorectal cancer (34596,39042,39349). Other contradictory research suggests that postmenopausal females who take calcium 1000 mg daily plus vitamin D 400 IU daily do not have a reduced risk of developing colorectal cancer (14290); however, this finding may not be reliable due to the high baseline intake of calcium in study participants. The reason for these conflicting findings is not entirely clear. Vitamin D might be an important factor. People with lower than average vitamin D levels do not seem to get any benefit from calcium supplements (12118). Also, one meta-analysis of previous trials suggests that taking calcium 1200 mg daily reduces the risk of colorectal adenomas in people with a normal BMI, but not in those who are overweight or obese (99715). Despite this conflicting evidence, the US Food and Drug Administration (FDA) approved a qualified health claim in 2005 stating that calcium supplements may reduce the risk of colorectal cancer and colorectal adenomas. However, the FDA has determined that there is little scientific evidence to support this claim (102366).
• Fetal bone mineralization. If calcium intakes are low during pregnancy, oral calcium seems to be beneficial for increasing fetal bone density. Details: With low dietary calcium intake (less than 562 mg elemental calcium daily) during pregnancy, calcium supplementation increases fetal bone mineralization and density. However, calcium supplementation does not offer any additional benefit if calcium intakes are adequate (3263,3264).
• Hypertension. Oral calcium seems to reduce blood pressure by a small amount in adults with or without hypertension. However, it is unclear if this reduction is clinically significant. Details: Many clinical trials and observational studies, including a meta-analysis of 18 high-quality clinical trials, show that intake of calcium supplements or dietary calcium modestly reduces systolic blood pressure in patients with or without hypertension, usually around 1-2 mmHg. Calcium seems to be more effective for certain subpopulations of patients, such as those who are salt-sensitive or have low baseline dietary calcium intake (945,972,974,976,984,1818,1819,1820,1821,6852)(13138,14406,38803,39063,39094,39221,113920,113925). However, a large-scale clinical trial in postmenopausal females shows that taking vitamin D (cholecalciferol) 400 IU daily in combination with elemental calcium 1000 mg daily does not lower blood pressure or reduce the risk of developing hypertension (16714). Additionally, a meta-analysis of 8 clinical trials shows that taking calcium in combination with vitamin D for up to 7 years has no effect on blood pressure (98861). The validity of this finding is limited by the poor methodological quality of the included studies. Some observational research suggests that calcium can reduce the risk for hypertension. Population research in females aged 45 years and older suggests that higher intake of calcium from both diet and supplemental sources is linked to a lower risk of developing hypertension when compared to lower calcium intake (14265). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim stating that calcium supplements may reduce the risk of hypertension. However, the FDA has concluded that this claim is based on supporting, rather than conclusive, evidence (102367). Research evaluating the effect of calcium supplementation during pregnancy on the child's blood pressure has yielded conflicting findings. A systematic review of 2 clinical studies and 3 observational studies found that calcium intake during pregnancy is associated with a 1-2 mmHg reduction in the systolic blood pressure of the offspring between the ages of 1-7 years (38852). However, a separate meta-analysis of 3 clinical studies shows that calcium intake during pregnancy does not reduce systolic or diastolic blood pressure in the offspring (113923).
• Osteomalacia. Oral calcium seems to reverse osteomalacia caused by very low calcium intakes. Details: Osteomalacia is commonly caused by vitamin D deficiency; however, very low calcium intake can also lead to osteomalacia in children and adults. Calcium supplementation can reverse osteomalacia caused by calcium deficiency. Along with appropriate vitamin D supplementation, individuals at risk of osteomalacia need sufficient calcium intake (94819).
• Pre-eclampsia. Oral calcium seems to reduce the risk of pre-eclampsia, especially in high-risk individuals and those with low baseline dietary calcium intake. Details: Although there is some conflicting evidence (971,38756), most clinical research shows that taking calcium orally 1-2 grams daily reduces the risk of pre-eclampsia (973,1833,8828,39043,39319,39426,97348,113919). A large clinical trial of 11,000 pregnant individuals in India and Tanzania shows that supplementation with 500 mg daily is similarly effective to 1500 mg daily (113908). Multiple meta-analyses which include 16-30 clinical studies have found that varying doses of calcium supplementation reduce the relative risk of pre-eclampsia by 46% to 51% when compared with placebo (97348,113909,113919). One of these meta-analyses found that for every 19 females treated with calcium, one episode of pre-eclampsia would be avoided (97348). Additionally, one of these meta-analyses found that calcium reduces the relative risk of pre-eclampsia by 51%, regardless of whether it is taken at a dose above or below 1000 mg daily (113919). Some research suggests that calcium supplementation may have a greater effect in individuals at high risk of pre-eclampsia or with low baseline dietary calcium intake, and when taken at greater than or equal to 20 weeks of gestation (15029,38497,97348,99714,113919). However, another meta-analysis of 30 clinical studies found a similar benefit of calcium in both high- and low-risk individuals (113919). A separate meta-analysis of 6 clinical studies conducted in China evaluated the benefits of calcium carbonate 500-600 mg daily taken in conjunction with aspirin 50-75 mg daily during pregnancy. This combination was associated with an 80% lower relative risk of pre-eclampsia and an 83% lower relative risk of pre-eclampsia with gestational hypertension when compared with routine care (113913). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim regarding the use of calcium supplements to reduce the risk of pregnancy-induced hypertension and pre-eclampsia. However, due to the limited and conflicting research available at that time, the FDA stated that this outcome was highly unlikely (102366). Since then, large, high-quality clinical research has supported this finding. In fact, in 2016 the World Health Organization (WHO) released a recommendation to prescribe oral calcium 1.5-2 grams daily during pregnancies at high risk of pre-eclampsia if dietary calcium intakes are low (97347).
• Pregnancy-induced hypertension. Oral calcium may reduce the risk of pregnancy-induced hypertension. Details: A meta-analysis of 17 clinical studies shows that calcium supplementation during pregnancy may reduce the relative risk of pregnancy-induced hypertension by 30% when compared with control (113909). A separate meta-analysis of 6 clinical studies conducted in China, which evaluated the benefits of calcium carbonate 500-600 mg daily taken in conjunction with aspirin 50-75 mg daily during pregnancy, shows that this combination reduces the relative risk of pregnancy-induced hypertension by 85% when compared with routine care (113913).
• Rickets. Oral calcium seems to reverse rickets caused by very low calcium intakes. Details: Rickets is commonly caused be vitamin D deficiency; however, very low calcium intake can also lead to rickets. Calcium supplementation can reverse rickets caused by calcium deficiency (94819). A small clinical study in children with nutritional rickets shows that taking calcium 500-2000 mg daily for 24 weeks improves radiographically measured rickets caused by calcium deficiency. Rickets seems to improve more rapidly with calcium 1000 mg compared to calcium 500 mg. However, increasing the calcium dose to 2000 mg daily is not more beneficial than calcium 1000 mg daily (98904).
• Tooth retention. Oral calcium with vitamin D seems to help with tooth retention in the elderly population. Details: A clinical trial in the elderly population shows that taking calcium citrate malate 500 mg daily along with vitamin D3 (cholecalciferol) 700 IU daily orally for 3 years reduces the risk of tooth loss by about 52% when compared with placebo (8816).

POSSIBLY INEFFECTIVE

• Breast cancer. Oral calcium, via supplementation or as part of the diet, does not seem to be beneficial for breast cancer prevention. Details: Although some studies disagree (15631,39041,95811,107237,113917), most population research suggests that increased calcium intake is not associated with overall breast cancer risk (15631,16715,98895,107236,107237,113917). However, one meta-analysis of observational studies shows that although higher total calcium intake is not associated with breast cancer risk, higher dietary calcium intake, specifically, may be associated with a slightly reduced risk (113917). Also, some analyses suggest that calcium intake may be associated with the risk for certain breast cancer sub-types. Some subgroup analyses suggest that calcium intake may reduce the risk of breast cancer in postmenopausal, but not pre-menopausal, adults (15631,107237) and that dietary calcium intake may reduce estrogen receptor(ER)-negative breast cancer, but not ER-positive breast cancer (107236). However, most research has not evaluated the effects of calcium supplementation or intake on breast cancer subtypes. The best evidence to date, from a large scale clinical trial (Women's Health Initiative), shows that taking vitamin D (cholecalciferol) 400 IU daily plus calcium 1000 mg daily for 7 years after menopause does not reduce the risk of developing invasive breast cancer at the end of the study and 5 years after the end of the intervention (16715,98895).
• Fractures. Although oral calcium prevents fractures in osteoporosis, most evidence shows that calcium does NOT prevent factures in people who do not have osteoporosis. See Osteoporosis discussion for more information on the use of calcium for this purpose. Details: Robust meta-analyses of mostly large, high-quality clinical studies show that calcium supplementation 500-1600 mg daily for 0.5-7 years with or without vitamin D does not reduce total fractures, hip fractures, vertebral fractures, or non-vertebral fractures in older adults without osteoporosis (95822,112486). A large-scale study in postmenopausal females aged 50-79 years who were enrolled in the Women's Health Initiative (WHI) suggests that calcium 1000 mg plus vitamin D 400 IU daily for 7 years only modestly improves bone mineral density (BMD) and does not significantly reduce fracture risk. This lack of effect may have been due to low adherence to the treatment regimen. In those who were 80% adherent, the combination of calcium plus vitamin D reduced the risk of hip fracture by about 29% (14282). Also, some clinical research shows that taking calcium carbonate 1000 mg and vitamin D 400 IU for 5 years does not attenuate loss of height after menopause when compared with placebo (95810). Additional meta-analyses of clinical and observational evidence suggest that calcium supplementation is not associated with a reduced risk of vertebral or nonvertebral fractures, such as hip fractures (38589,38888,98895). Some other research has suggested that calcium in combination with vitamin D reduces fracture risk in older patients without osteoporosis (980,1836,8818,12930,12933,12952,38849,102145,107235); however, this research is confounded by a number of variables, including the presence of hormonal therapy and differing levels of fracture risk at baseline (1836,8818,95822). Conflicting findings on this topic might also be due to genetic differences in patient populations. A population analysis of the WHI study found that, in older females with the lowest genetic susceptibility to low BMD, taking calcium with vitamin D is associated with a reduction in fracture risk. However, in females with a higher genetic susceptibility to low BMD, there is no association between supplementation and fracture risk. This might be because individuals with a lower susceptibility to low BMD are also more responsive to calcium and vitamin D supplementation (97357). As of April 2018, the U.S. Preventative Services Task Force (USPSTF) concludes that there is insufficient evidence to determine whether supplementing with vitamin D >400 IU daily along with calcium >1000 mg daily is safe and effective for preventing fractures in community dwelling adults without vitamin D deficiency, osteoporosis, or a history of fracture. USPSTF recommends against supplementing with calcium 1000 mg daily or less along with vitamin D 400 IU daily or less for preventing primary fractures in community-dwelling postmenopausal females (95695).
• Obesity. Oral calcium does not seem to improve weight loss in adults or children with overweight or obesity. Details: Observational research has found that adults and children with low calcium intake are more likely to gain weight, have a higher body mass index (BMI), and be overweight or obese when compared to people with high calcium intake (12124,12125,12126,12127,14265). Additional observational research has found that increasing calcium intake is associated with weight loss in females; the results in males have been conflicting (12127,15602,15603). Despite these findings from observational research and a few small clinical studies (12128,15397,14438,98905,113918), most clinical research has found that increased calcium intake does not increase weight loss (12052,13138,15396,15399,38985,39004,97356). A meta-analysis of 20 clinical studies shows that daily dietary and supplemental calcium intake that meets the dietary reference intake (DRI) of 1000 mg or more daily does not increase weight loss in overweight individuals or patients with obesity when compared with intake below the DRI (95813). An older meta-analysis of 13 clinical trials also shows that increased dietary and supplemental calcium intake does not increase weight loss (15605).
• Overall mortality. Oral calcium does not seem to reduce overall mortality. Details: While some population research has found that calcium taken in combination with vitamin D in older females is associated with a lower risk of death (97353), most evidence shows that calcium, with or without vitamin D, has no effect on all-cause mortality (93533,97308,113584).

INEFFECTIVE

• Cardiovascular disease (CVD). Oral calcium does not reduce the risk of developing CVD and may actually increase risk in some patients. Details: Clinical research shows that calcium does not decrease CVD risk. Several separate meta-analyses of clinical and population research involving over 50,000 patients show that taking calcium 600-1200 mg daily for up to 7 years does not reduce the risk of CVD-related outcomes, including stroke and myocardial infarction, cardiovascular death, or overall mortality (39018,91350,92994,93533,97308,98902,107231,107233). No association was found between total dietary or supplemental calcium intake with or without vitamin D and the risk of CVD or mortality (91350,93533,97308). In fact, some population and clinical research has found that when calcium is used alone or with vitamin D, there is an INCREASED risk of CVD and coronary heart disease (38077,107233). However, other clinical research disagrees (93533). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years increases the risk of CVD and coronary heart disease by 1.1-1.2 times when compared with control. However, the majority of the included research evaluated postmenopausal females and it is unclear if this finding is applicable to other populations (107233).
• Chemotherapy-induced peripheral neuropathy. Intravenous calcium does not prevent nerve pain in patients given oxaliplatin. Oral calcium has not been evaluated for this purpose. Details: While pooled analyses of cohort studies and randomized controlled trials suggest that calcium and magnesium infusion decreases the incidence of oxaliplatin-induced neurotoxicity, a meta-analysis of only randomized controlled trials shows that the infusion has no effect in preventing neurotoxicity (90028,90029,90031). Additionally, clinical trials show that administering calcium gluconate 1 gram with magnesium sulfate 1 gram intravenously immediately before, or before and after, the administration of a single oxaliplatin cycle (90005), or over the entire 6-cycle course of oxaliplatin, does not improve symptoms of neurotoxicity when compared with placebo (96474).
• Myocardial infarction (MI). Oral calcium does not prevent MI. When taken in the absence of vitamin D, oral calcium may increase the risk of MI. Details: Population research has found that increased dietary intake of calcium is associated with a decreased risk of MI (91350). However, a 2010 meta-analysis of clinical research shows that taking calcium at a dose of at least 500 mg daily is associated with an approximate 30% INCREASE in the risk of MI in patients over the age of 40. According to this analysis, one additional case of MI will occur for every 69 patients that take calcium for 5 years (17482). A more recent meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years increases the risk of MI by 1.2 times when compared with control. However, the majority of the included research studied postmenopausal females and it is unclear if this finding is applicable to other populations (107233) In contrast, other meta-analyses of clinical research have shown that taking calcium for up to 7 years is NOT associated with an increased risk of MI, including a meta-analysis that only included postmenopausal females (93533,107231). Reasons for these discrepancies are not entirely clear. It may relate to whether calcium is taken as monotherapy or in combination with vitamin D. When taken with vitamin D, which is commonly recommended, calcium supplementation does not appear to be associated with an increased risk of MI in postmenopausal females (93533). Also, the association between calcium supplementation and MI risk may be influenced by the amount of calcium consumed as part of the diet. Supplementation with calcium may be associated with an increased risk of MI in people with dietary calcium intake above 805 mg daily, but not in those with dietary calcium intake below 805 mg daily (17482)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. It is unclear if oral calcium is beneficial for alcohol use disorder. Details: Preliminary clinical research shows that taking calcium carbonate 800 mg and vitamin D 200 IU orally daily for 14 days modestly reduces alcohol craving scores and withdrawal scores when compared with placebo in adults with alcohol dependence that are undergoing withdrawal. Taking calcium carbonate did not reduce the need for diazepam; however, the study may have been inadequately powered to detect a difference between groups (107234).
• Atherosclerosis. It is unclear if oral calcium is beneficial for atherosclerosis. Details: A population study has found that taking calcium 1.2 grams daily for 3 years has no effect on carotid intima thickness or carotid atherosclerosis incidence. A total calcium intake (dietary and supplemental) of at least 1794 mg daily in older females may be associated with a decreased risk of carotid atherosclerosis when compared with a total calcium intake below 1010 mg daily (97351).
• Autism spectrum disorder. It is unclear if oral calcium during pregnancy is beneficial for reducing the odds of autism spectrum disorder in the offspring. Details: A small observational study found that calcium supplementation during pregnancy is associated with a 52% reduced odds of an autism spectrum disorder in the offspring (98900).
• Brain tumor. It is unclear if dietary calcium intake is associated with risk of brain tumor. Details: A meta-analysis of 4 case-control studies has found that higher dietary calcium intake is associated with a lower odds of brain tumor when compared with lower dietary intake (113922). The validity of this finding is limited by the exploratory nature of the included studies, which analyzed all dietary ingredients for any potential associations.
• Cancer. Oral calcium alone does not seem to prevent cancer. It is unclear if oral calcium with vitamin D is beneficial for preventing cancer. Details: Taking calcium alone does not seem to significantly reduce the risk of cancer (12118,15629). The role of calcium in cancer prevention when taken along with vitamin D is controversial, as conflicting results exist. One clinical trial shows that healthy postmenopausal females who take supplemental calcium 1400-1500 mg daily plus vitamin D3 (cholecalciferol) 1100 IU daily have a 60% lower relative risk for developing cancer of any type. Approximately 25 postmenopausal females would need to take this combination for 4 years to prevent one occurrence of cancer (15629). However, a more recent clinical study shows that healthy postmenopausal females who take supplemental calcium 1500 mg daily plus vitamin D3 (cholecalciferol) 2000 IU daily do not have a reduced risk of cancer at 4 years (93943). Reasons for the disparate results are not entirely clear. The discrepancies do not appear to be related to baseline vitamin D levels or different study populations. It is possible that, given the 10-year time lapse between the two publications, the discrepancies result from differences in cancer detection capability. Also, since cancer risk was a secondary outcome measure in the earlier study and a primary outcome measure in the more recent study, it is possible that the discrepancies result from differences in statistical methodologies. The effect of vitamin D and calcium on cancer risk in males and younger patients is not known. There is also interest in using calcium for reducing the risk of hematological malignancies. An analysis of the Women's Health Initiative study shows that taking calcium 1000 mg daily in combination with vitamin D3 400 IU for up to 10 years is associated with a 20% reduction in the risk of hematologic malignancies when compared with placebo. However, no effect on hematologic malignancy related mortality was seen (97354).
• Depression. It is unclear if oral calcium is beneficial for depression prevention. Details: Population research has found no association between a higher dietary intake of calcium and the risk of depression when compared with a lower dietary intake of calcium (96480).
• Diabetes. It is unclear if dietary calcium intake is associated with type 2 diabetes risk. Details: Some population research has found that a higher intake of calcium from the diet or supplements, alone or in combination with vitamin D, is associated with a lower risk of developing type 2 diabetes when compared with lower calcium intake (14265,16713,96473,113929). One meta-analysis of cohort and cross-sectional studies found that the highest level of dietary calcium intake is associated with an 18% relative reduction in risk of type 2 diabetes when compared with the lowest level of intake. A dose-response analysis suggests that each 300, 600, and 1000 mg per day increase in dietary calcium intake is associated with a 7%, 14%, and 23% reduced risk of type 2 diabetes, respectively (113929). However, population research is often limited by confounding variables. For example, one analysis suggests that any beneficial effect might be influenced by concomitant magnesium intake (96473,113929), while another suggests that any benefit from increased intake may be more pronounced in females, adults aged 50 years or older, and Asian populations (113929). Furthermore, other population research has found that serum calcium levels higher than 9.6 mg/dL are associated with greater risk of developing diabetes in Chinese adults with osteoporosis (95815).
• Dyslipidemia. It is unclear if oral calcium is beneficial for dyslipidemia. Details: One clinical study in adults with mild to moderate hypercholesterolemia shows that adding calcium carbonate 400 mg three times daily to a low-fat diet (American Heart Association Step 1) for 6 weeks reduces low-density lipoprotein (LDL) cholesterol levels by 4% and increases high-density lipoprotein (HDL) cholesterol levels by 4% when compared with the low-fat diet and placebo (2557). In contrast, a clinical study in females with dyslipidemia shows that taking calcium 800 mg daily for 2 years INCREASES total cholesterol levels and carotid intima-media thickness in postmenopausal, but not premenopausal, females when compared with placebo (97350). Calcium supplementation has also been evaluated in combination with vitamin D. A meta-analysis of randomized controlled trials including adults with normolipidemia and dyslipidemia shows that taking calcium 500-2000 mg daily and vitamin D 200-7142 IU daily modestly improves HDL cholesterol and triglyceride levels, but not LDL cholesterol levels, when compared with placebo. Subgroup analyses suggest that calcium and vitamin D supplementation is most beneficial in patients with dyslipidemia at baseline (107227). The relationship between dietary calcium intake and serum lipid levels has also been evaluated in observational research. A meta-analysis of 7-11 observational studies found that dietary calcium intake is not associated with total cholesterol levels, although small differences in individual lipid parameters were identified. Additionally, a meta-analysis of 4-9 observational studies suggests that calcium intake is not associated with the risk of developing hypertriglyceridemia, hypercholesterolemia, or low HDL. A subgroup analysis found that higher calcium intake may be associated with lower triglyceride levels in Asian populations (113927). Overall, these findings are limited by significant heterogeneity and the cross-sectional nature of the included studies.
• Dysmenorrhea. It is unclear if oral calcium is beneficial for reducing pain associated with dysmenorrhea. Details: Clinical research shows that taking calcium carbonate 1000 mg with vitamin D 5000 IU daily for three menstrual cycles does not reduce pain when compared with placebo in patients with primary dysmenorrhea (95821). However, calcium carbonate 1000 mg taken alone seems to reduce pain when compared with placebo.
• Endometrial cancer. It is unclear if oral calcium is beneficial for endometrial cancer prevention. Details: A meta-analysis of population research suggests that calcium supplements may reduce the risk of endometrial cancer, but dietary calcium does not seem to have any effect (38893).
• Exercise-induced muscle damage. It is unclear if oral calcium is beneficial for reducing exercise-induced muscle damage. Details: A very small clinical study in resistance-trained adults shows that taking calcium carbonate 500 mg 4 times daily for 3 weeks does not attenuate exercise-induced muscle damage from bench presses when compared with placebo (113933). This study may have been inadequately powered to detect a difference between groups.
• Fall prevention. It is unclear if oral calcium with vitamin D is beneficial for preventing falls. Details: Research suggests that calcium in combination with vitamin D, but not calcium alone, might prevent falls by decreasing body sway and normalizing systolic blood pressure (6362,11939,39038). Some experts think the combination of calcium and vitamin D may be important (11916). Preliminary clinical research in adults residing in a health care facility shows that taking vitamin D supplements while increasing dietary calcium and protein for 2 years reduces falls by 11% when compared with standard diets. Intervention diets were supplemented with milk, yogurt, and cheese to provide calcium 1142 mg and protein 69 grams daily (107235). There might also be different effects in females compared to males. In one study, females aged 65 years or older who took vitamin D 700 IU plus calcium citrate 500 mg daily over a 3-year period had a 46% lower risk of falling. However, this combination did not decrease falls in males (14291).
• Fluorosis. Oral calcium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking calcium orally, in combination with ascorbic acid (vitamin C) and vitamin D, seems to be effective for reducing excessive fluoride levels in children and improving symptoms of fluorosis in children aged 6-12 years (990).
• Heart failure. It is unclear if oral calcium in combination with vitamin D is beneficial for preventing heart failure. Details: Based on a secondary analysis of a large-scale clinical trial (Women's Health Initiative), taking calcium 1000 mg with vitamin D 400 IU daily does not reduce the risk of heart failure in the overall population or in individuals at high risk. However, in a subgroup of postmenopausal females without risk factors for heart failure, calcium and vitamin D supplementation might reduce the risk of developing heart failure by about 37% (97307).
• Lead toxicity. It is unclear if oral calcium is beneficial for reducing blood levels of lead. Details: Lead is mobilized along with calcium from bone during pregnancy and lactation, resulting in increased serum concentrations of lead. One clinical study suggests that calcium supplementation does not significantly decrease these elevated lead concentrations (1586). However, another clinical study suggests that taking calcium reduces blood lead levels by 11% when compared with placebo, with greatest effects observed in those with high baseline levels of lead (38957).
• Lyme disease. Although there is interest in using oral calcium for Lyme disease, there is insufficient reliable information about the clinical effects of calcium for this condition.
• Metabolic syndrome. It is unclear if oral calcium alone or with vitamin D is beneficial for metabolic syndrome prevention. Details: Population research has found that a higher intake of calcium from diet and supplements alone, or in combination with vitamin D, is associated with a lower risk of developing metabolic syndrome when compared with lower calcium intake (14265,16713).
• Nephrotic syndrome. It is unclear if oral calcium with vitamin D is beneficial for preventing nephrotic syndrome. Details: Clinical research shows that taking calcium 500-1000 mg daily for 3 months in combination with vitamin D3 60,000 IU daily or weekly for 4 weeks has no effect on bone mineral density or the risk of relapse in children with steroid-sensitive nephrotic syndrome (97355).
• Nonmelanoma skin cancer. It is unclear if oral calcium is beneficial for preventing keratinocyte carcinomas. Details: In middle aged and older adults recently diagnosed with a colorectal adenoma, clinical research shows that taking calcium 1200 mg daily as calcium carbonate for 3-5 years does not reduce the incidence of keratinocyte cancer when compared with placebo over a median of 8 years. A sub-group analysis shows that taking calcium alone or with vitamin D3 1000 IU daily reduced the risk of invasive cutaneous squamous cell carcinoma by a moderate amount, but had no effect on the risk of basal cell carcinoma (104622).
• Oral mucositis. When used in combination with fluoride treatments, a calcium phosphate mouth rinse seems to prevent and reduce mucositis-related pain in patients undergoing hematopoietic stem cell transplantation (HSCT). Details: A small clinical study in patients undergoing HSCT shows that using a particular mouth rinse (Caphosol, EUSA Pharma) containing calcium phosphate, in combination with fluoride treatments, reduces days of mucositis, the duration of pain, and the dose and days of morphine used when compared with placebo and fluoride treatment (38611).
• Ovarian cancer. It is unclear if oral calcium is beneficial for ovarian cancer prevention. Details: An older meta-analysis of 12 cohort studies found that dietary calcium intake is not associated with a reduced risk of ovarian cancer (38792). However, a more recent pooled analysis of 15 cohort and case-control studies has found that the highest intake of dietary or dairy calcium is associated with a 20% lower risk of ovarian cancer when compared to the lowest intake (97349).
• Postpartum depression. It is unclear if oral calcium is beneficial for reducing postpartum depression risk. Details: Preliminary clinical research shows that taking calcium 2 grams daily beginning at 11-21 weeks gestation reduces depression at 12 weeks postpartum when compared with placebo. However, no benefit is seen at 6 weeks postpartum (39447).
• Pregnancy-related leg cramps. It is unclear if oral calcium is beneficial for preventing leg cramps during pregnancy. Details: A small clinical study shows that taking calcium 1 gram twice daily (as a mixture of salts) for 2 weeks can reduce pregnancy-related leg cramps during the second half of pregnancy when compared with no treatment (2567).
• Prematurity. It is unclear if supplemental calcium is beneficial for the growth and development of preterm infants. Details: A small clinical study in preterm infants consuming human milk shows that supplementation with calcium 45 mg/kg daily and phosphorus 25 mg/kg daily does not affect infant weight, length, head circumference, or risk of osteopenia after 6 weeks when compared with human milk alone (113924). However, the duration and size of this study may have been too limited to detect any difference between groups.
• Preterm labor. It is unclear if oral calcium reduces the risk of preterm labor. Details: A meta-analysis of 10 clinical studies shows that taking calcium supplements during pregnancy does not reduce the risk of preterm labor when compared with placebo (113909). A separate meta-analysis of 7 clinical studies conducted in China, which evaluated the benefits of calcium carbonate 500-600 mg daily taken in conjunction with aspirin 50-75 mg daily during pregnancy, shows that this combination reduces the relative risk of preterm labor by 74% when compared with routine care (113913).
• Prostate cancer. It is unclear if oral calcium is beneficial for prostate cancer prevention. Details: Some clinical research shows that taking calcium 1200 mg daily might decrease the risk of developing prostate cancer (14133). However, some epidemiological research suggests that consuming very high doses of calcium, over 2000 mg daily, might actually increase the risk of developing prostate cancer (14134). Some epidemiological research also suggests that doses greater than 1500 mg daily increase the risk of poorly differentiated, clinically advanced, and fatal prostate cancer (14132). Consumption of dairy products has also been weakly linked to a modest increase in risk of prostate cancer (98894). However, contradictory research suggests that there is no association between dietary intake of calcium and overall risk of prostate cancer (14131,14132,104630).
• Stroke. It is unclear if oral calcium is beneficial for stroke prevention. Details: Some population research has found that increasing dietary calcium intake is associated with a decreased risk of ischemic stroke (4822,38678). However, other population research has found that increasing dietary calcium intake is not associated with a decreased risk of stroke (91350). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years does not affect the risk of stroke when compared with control. However, the majority of the included research evaluated postmenopausal females, and it is unclear if this finding is applicable to other populations (107233).
• Vertigo. Oral calcium with vitamin D might reduce positional vertigo; the effect of calcium when used alone is unclear. Details: A large clinical study in adults with recurrent benign paroxysmal positional vertigo shows that taking calcium 500 mg and vitamin D 400 IU twice daily for one year reduces annual recurrence of vertigo by 27% when compared with no treatment. The number needed to treat to prevent vertigo was 3.7 (103681). It is unclear if this benefit is due to vitamin D, calcium, or the combination. More evidence is needed to rate calcium for these uses.

(Read more about CALCIUM)

POSSIBLY INEFFECTIVE

• Athletic performance. Taking oral choline before exercise does not improve athletic performance. Details: Clinical research in trained athletes shows that taking oral choline 2.43 grams as a single dose does not delay fatigue during endurance sports when compared with placebo (5164). Other clinical research in untrained adults shows that taking oral choline 8.425 grams or 50 mg/kg once prior to participating in exhaustive, load-carrying exercise does not improve dexterity, upper or lower body strength, grip strength, or run time-to-exhaustion following exercise when compared with placebo (42229,42237).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral choline is beneficial in patients with age-related cognitive decline. Details: Small clinical studies in adults with memory loss shows that taking choline 2 grams four times daily orally for 21 days does not improve memory when compared with placebo (5170). Observational research in adults over 60 years of age has found that intake of choline 187-399.5 mg daily is associated with a 33% to 42% reduced odds of low cognitive function when compared with intake of less than 187 mg daily. Intake of more than 399.5 mg daily was not associated with low cognitive function when compared with less than 187 mg daily (109100).
• Allergic rhinitis (hay fever). It is unclear if oral choline is beneficial in patients with allergic rhinitis. Details: Preliminary clinical research shows that taking oral choline, as tricholine citrate, 500 mg three times daily for 8 weeks is less effective than intranasal budesonide 200 mcg twice daily for reducing symptoms of allergic rhinitis (42252).
• Alzheimer disease. Although there has been interest in using oral choline for Alzheimer disease, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Asthma. Small clinical studies suggest that oral choline may modestly improve symptoms in patients with asthma. Details: Preliminary clinical research shows that taking choline 500-1000 mg orally three times daily for 3-4 months decreases the severity of symptoms, the number of symptomatic days, and the need to use bronchodilators in patients with asthma when compared with placebo (5165,5166). Preliminary data also shows that choline 3 grams daily might be more effective than 1.5 grams daily (5165).
• Autism spectrum disorder. Oral choline has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination of donepezil 2.5-5 mg daily and choline bitartrate 350 mg daily for 12 weeks improves receptive language skills, but no other outcomes, for up to 6 months after treatment when compared with placebo in children aged 5-10 years with autism spectrum disorder. Also, adolescents aged 11-16 years experienced no benefits, and some experienced an increase in behavioral symptoms, such as irritability (103571). It is unclear if this effect is due to choline, donepezil, or the combination.
• Breast Cancer. It is unclear if dietary intake of choline reduces the risk of breast cancer. Details: A meta-analysis of 6 low to moderate-quality observational studies suggests that neither high nor low dietary intake of choline is associated with breast cancer risk. This finding is largely influenced by inclusion of the European Prospective Investigation into Cancer and nutrition (EPIC) cohort study, which analyzed data from over 300,000 subjects. However, subanalysis of 3 case-control studies suggests that high dietary intake of choline may be associated with a decreased risk of breast cancer when compared with low choline intake (111416). The interpretation of these findings is limited by the heterogeneity of the included studies, self-reported data, and a small number of studies.
• Bronchitis. Although there has been interest in using oral and inhaled choline for bronchitis, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Cancer. It is unclear if dietary choline intake reduces the risk for cancer. Details: A meta-analysis of 11 low-quality population studies has found that high dietary intake of choline is associated with an 18% lower risk of cancer when compared with low choline intake. High dietary intake of both choline and betaine was associated with a 40% lower risk of cancer (97390).
• Cardiovascular disease (CVD). It is unclear if dietary choline intake reduces the risk of CVD or improves outcomes in patients with CVD. Details: A meta-analysis of population research has found that high intake of dietary choline is not associated with a lower risk of coronary artery disease, stroke, or mortality when compared with a diet low in choline (97388). A more recent population study has found that energy-adjusted total choline intake is not associated with the incidence of CVD over ten years. However, the highest intake of free choline is associated with a 34% reduced risk of CVD when compared with the lowest intake (109104).
• Cerebellar ataxia. It is unclear if oral choline is beneficial in patients with cerebellar ataxia. Details: Despite some anecdotal reports suggesting that taking choline improves motor function, preliminary clinical research shows that taking choline 4-5 grams orally daily for 4 days to 6 weeks does not reduce cerebellar ataxia (5161,5173,23679).
• Cognitive function. It is unclear if oral choline is beneficial for improving cognitive function in healthy adults. Details: Preliminary clinical research shows that taking a single dose of choline 50 mg/kg orally prior to participating in an exhaustive, load-carrying task does not improve reaction time, reasoning, memory, or serial addition and subtraction ability following the task when compared with placebo (42237). Also, preliminary clinical research in patients requiring long-term total parenteral nutrition (TPN) shows that adding choline chloride 2 grams daily to TPN for 24 weeks might improve delayed visual memory, but does not improve other measures of cognitive performance, when compared with TPN alone (42232).
• Cirrhosis. Although there has been interest in using oral choline for cirrhosis, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Complex partial seizures. Although there has been interest in using oral choline for complex partial seizures, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Dementia. Although there has been interest in using oral choline for dementia, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Depression. It is unclear if oral choline is beneficial for the treatment or prevention of depression. Details: Observational research has found that dietary choline intake of at least 198 mg daily is associated with a 32% to 43% decreased risk of depressive symptoms when compared with intakes of less than 198 mg daily (109106). It is unclear if choline supplementation is beneficial for depression.
• Diabetes. It is unclear if oral choline is beneficial for the treatment or prevention of type 2 diabetes; the available research is conflicting. Details: Preliminary clinical research shows that taking oral choline bitartrate 1000 mg daily for 2 months does not affect coagulation parameters or levels of triglycerides, low-density lipoprotein (LDL) cholesterol, or high-density lipoprotein (HDL) cholesterol in patients with type 2 diabetes (103569). Choline has also been evaluated for the prevention of type 2 diabetes. In Finnish males, observational research has found that dietary intake of total choline at levels of more than 482 mg daily, especially as phosphatidylcholine, is associated with a 25% lower risk of developing type 2 diabetes over the following 19.3 years when compared with intakes of less than 382 mg daily (103567). However, in males and females in the US, additional observational research has found no association between dietary choline and risk of type 2 diabetes over a mean of 9 years (103570). In addition, a sub-analysis found that the highest intakes of choline (a median of 487 mg daily) were associated with a 54% higher risk of type 2 diabetes among females, but not males, when compared with the lowest intakes (a median of 175 mg daily) (103570). Population research in patients with diabetes has found that an intake of dietary choline in amounts of at least 279 mg daily is associated with a 2.1-fold increased odds of diabetic retinopathy in females, but not males, when compared with an intake less than 206 mg daily (109102). It is unclear if choline itself is responsible for the increased odds of diabetic retinopathy in this population.
• Fetal alcohol spectrum disorders (FASD). It is unclear if oral choline improves cognition in children with fetal alcohol spectrum disorders (FASD). Details: Clinical research in children aged 2.5-5 years with FASD shows that taking oral choline bitartrate, providing choline 500 mg, daily for 9 months does not improve global cognitive development or hippocampal-dependent memory when compared with placebo. However, a subgroup analysis of only children aged 2.5-4 years suggests that choline may improve hippocampal-dependent memory (92112). Follow-up of this study at 7 years shows that choline improves motor speed and suggests a trend towards improved color naming, which are components of executive functioning testing, when compared with placebo (111745). The validity of these findings is limited by the high rate of patient discontinuation which limits statistical power. A small clinical trial in children 5-10 years old with FASD shows that taking oral glycerophosphocholine, providing choline 625 mg, daily for 6 weeks does not improve cognitive function, executive function, attention, or hyperactivity when compared with placebo (97389).
• Hepatitis. Although there has been interest in using oral choline for hepatitis, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Huntington disease. Although there has been interest in using oral choline for Huntington disease, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Hypertension. It is unclear if oral choline is beneficial for the prevention or treatment of hypertension. Details: Population research has found that every 100-mg increase in daily dietary choline intake is associated with a 15% decreased risk of developing hypertension over the next 4.6 to 9.1 years (109098). However, it is unclear if any benefits are specifically related to dietary choline or whether choline supplementation is beneficial.
• Infant development. It is unclear if oral choline intake during pregnancy is beneficial for infant development; the available research is conflicting. Details: Two observational studies have found that higher intake of choline during the second and third trimesters of pregnancy is associated with improvement in offspring cognitive development and visual memory at the age of 18 months and 7 years, respectively, when compared with lower choline intake (94654,94657). One of these studies found that each 1 mcmol/L increase in maternal blood levels of choline at 16 weeks' gestation was associated with a 2.23-point increase in cognitive skill score based on the Bayley Scales of Infant Development (BSID-III) at 18 months of age (94657). Also, some observational research has found that higher plasma levels of choline during pregnancy are associated with higher processing speed and decreased social withdrawal at 4 years of age in the offspring (109101). In contrast, 3 observational studies have found that higher intake of choline during pregnancy, as well as higher maternal and cord blood levels of choline, are not associated with improved offspring intelligence at 5 years of age or cognitive performance at 3 or 7 years of age (94654,94655,94656). However, many of these observational studies, including those with positive findings, included populations with a mean intake of choline that was below the recommended adequate intake of 450 mg daily (94654,94656). It's possible that higher intake of choline is needed to observe a benefit; however, research on the effects of choline supplementation is limited. One small clinical trial shows that taking choline 930 mg daily during the third trimester modestly improves sustained attention in the child at 7 years of age when compared with taking 480 mg daily (109105).
• Metabolic syndrome. It is unclear if oral choline is beneficial in patients with metabolic syndrome. Details: Preliminary clinical research in adults with metabolic syndrome shows that taking oral choline 400 mg daily for 4 weeks does not decrease body weight, blood pressure, plasma glucose levels, or low-density lipoprotein (LDL) cholesterol levels, or increase high-density lipoprotein (HDL) cholesterol levels, when compared with baseline (105731).
• Neural tube birth defects. It is unclear if oral choline intake is beneficial for preventing neural tube defects. Details: Population research has found that females who have a high dietary choline intake around the time of conception have a lower risk of having offspring with a neural tube defect when compared to those with lower intake (13134).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral choline is beneficial in patients with nonalcoholic fatty liver disease (NAFLD). Details: A cross-sectional analysis of results from observational and clinical research shows that low dietary intake of choline is associated with increased fibrosis in postmenopausal adults with NAFLD, but not in children, males, or premenopausal adults with NAFLD. Dietary choline intake was not associated with steatosis severity in any patient subgroup (92109).
• Schizophrenia. Although there has been interest in using oral choline for schizophrenia, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Tourette syndrome. Although there has been interest in using oral choline for Tourette syndrome, there is insufficient reliable information about the clinical effects of choline for this purpose.
• TPN-associated hepatic steatosis. It is unclear if intravenous choline is beneficial in patients with TPN-associated hepatic steatosis. Details: In patients receiving long-term total parenteral nutrition (TPN), plasma levels of choline can decrease. Small, low-quality clinical studies show that administering intravenous choline 1-4 grams daily for 24 weeks improves some markers of TPN-associated hepatic steatosis when compared with baseline or placebo (5174,42235). More evidence is needed to rate choline for these uses.

(Read more about CHOLINE)

POSSIBLY EFFECTIVE

• Common cold. Taking echinacea orally while still healthy may help prevent the common cold, but the benefit is probably modest. Echinacea does not seem to have a significant benefit for treating colds that have already developed. Details: Three meta-analyses show a 10% to 58% reduction in the risk of developing a cold when taking various forms of echinacea (17520,17522,95652). A large clinical study shows that adults who use a specific echinacea extract (Echinaforce, A. Vogel Bioforce AG) 0.9 mL three times daily (2400 mg echinacea daily) for 4 months, with an increase to 0.9 mL five times daily (4000 mg echinacea daily) at the first sign of a cold, have 59% fewer cold episodes and 26% fewer days with cold symptoms than those taking placebo (18225). Many smaller studies have shown a non-significant trend toward a prophylactic benefit, but they were likely underpowered to detect a statistically significant difference (3282,6386,17521,95652). Research in adults who are deliberately infected with cold viruses shows that taking echinacea products either does not reduce the incidence of colds, or has a limited effect which is not statistically significant. Products used include E. angustifolia root extract 300 mg three times daily for 7 days before and 5 days after experimental infection (13419), an alcoholic extract of E. purpurea above-ground parts (EchinaGuard, Madaus AG) 2.5 mL three times daily for 7 days before and 7 days after experimental infection (12354), or echinacea 300 mg three times daily for 14 days before and 5 days after experimental infection (8228). These studies are small and have methodological problems. Some small clinical studies have suggested that taking E. purpurea extracts as a tincture or tea to treat the common cold modestly reduces symptom severity and reduces cold duration by a couple of days (6384,10320,10802,12355,14419,20062,111530). Specific products used in these studies include Echinilin by Inovobiologic Inc., and Echinacin and EchinaGuard by Madaus AG (10320,10802,12355,20062). In contrast, higher quality clinical research shows that taking E. purpurea alone or with E. angustifolia does not reduce duration or severity of cold symptoms when compared with placebo (10800,11970,17519,20059). Echinacea has also been evaluated in children. Preliminary clinical research in healthy children 4-12 years old shows that taking a specific E. purpurea product (Echinaforce Junior, A. Vogel) 400 mg three times daily for 4 months reduces the occurrence of cold symptoms, respiratory complications (such as pneumonia and otitis media), and antibiotic prescriptions by 30%, 52%, and 62%, respectively, when compared with vitamin C 50 mg three times daily. Taking echinacea also reduces the average duration of symptoms during respiratory illness by an average of 1.4 days when compared with vitamin C (105719). However, other clinical research in children has found no benefit with a specific E. purpurea product (Echinacin, Madaus AG) (4989,95653).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Anxiety. It is unclear if oral echinacea reduces anxiety. Details: Preliminary clinical research shows that taking a specific E. angustifolia extract (ExtractumPharma ZRT) 40 mg once or twice daily for 7 days reduces anxiety scores on the State-Trait Anxiety Inventory scale when compared with placebo (20064,103233). This extract seems to be more effective in patients with high baseline anxiety scores (103233). A lower dose of 20 mg daily appears to be ineffective (20064). Conversely, a small clinical study in physically healthy adults with mild to moderate anxiety shows that taking the same E. angustifolia extract at doses of 20 or 40 mg twice daily for 6 weeks does not reduce anxiety when compared with placebo (106626).
• Athletic performance. It is unclear if oral echinacea improves athletic performance. Details: Preliminary clinical research in healthy, recreationally active males shows that taking echinacea (Puritan's Pride) 2 grams four times daily for 28 days increases serum erythropoietin levels and maximal oxygen consumption (VO2max) during exercise tests (20066). However, two small clinical studies in endurance trained athletes and in non-athletes with high aerobic fitness show that taking E. purpurea 8 or 16 grams once daily for 35 days in combination with other ingredients (Biomedical Research Lab), or taking E. purpurea (Puritan's Pride) 8 grams daily for 42 days, has no effect on erythropoietin levels, VO2max, or aerobic capacity (95651,101593). A meta-analysis of these and other small clinical trials in trained and recreational athletes shows that taking echinacea 8 grams orally daily for 28-42 days does not improve VO2max, hemoglobin, or erythropoietin levels when compared with placebo (114569). However, this analysis may have been inadequately powered to detect a difference between groups.
• Atopic dermatitis (eczema). Some evidence shows that an echinacea cream may be effective in mild disease, but it has not been compared to conventional treatments such as corticosteroids. Details: Preliminary clinical research in patients with mild atopic dermatitis shows that applying a cream containing echinacea (Linola Plus Cream, Dr. August Wolff GmbH & Co) 2-3 times daily for 12 weeks reduces symptoms such as erythema, edema, pruritus, and dryness when compared with a cream containing birch bark extract (Imlan Crème Pur, Birken AG). However, the echinacea product was no different to the comparator cream at the 4- and 8-week assessments, indicating that it might take up to 12 weeks to show benefit (97499).
• Attention deficit-hyperactivity disorder (ADHD). Although there has been interest in using oral echinacea for ADHD, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• Burns. Although there has been interest in using topical echinacea for burns, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral echinacea for CFS, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• Coronavirus disease 2019 (COVID-19). It is unclear if oral echinacea is beneficial for preventing or treating COVID-19. Details: A moderate-size open-label clinical study tested the effects of echinacea to prevent or treat respiratory viruses. This study of otherwise healthy adults in Bulgaria shows that taking echinacea extract (Echinaforce, A. Vogel AG) 2400 mg daily for cycles of 2, 2, and 1 months, with a 1-week break between each cycle, does not reduce symptomatic respiratory tract infections, including SARS-CoV-2, or respiratory virus detection overall when compared with usual care. However, echinacea extract does reduce the risk of a positive test for coronaviruses or SARS-CoV-2 by 48% and 63%, respectively. In patients who develop a symptomatic respiratory tract infection, this study also shows that taking the same echinacea extract 4000 mg daily for up to 10 days speeds viral clearance compared with usual care when all virus types were analyzed; however, clearance of SARS-CoV-2 was not improved. Echinacea may also reduce the number of days with a fever, but not other symptoms (111174). The validity of this study is limited by lack of blinding. Further, most patients were unvaccinated against COVID-19; it is unclear whether these results can be extrapolated to vaccinated patients. Echinacea has also been studied for long COVID. A moderate-size clinical trial in adults with recent COVID -19 infection shows that taking a combination product containing echinacea 30 mg, rose hips, zinc, and other ingredients orally daily for 2 months moderately improves fatigue scores when compared with placebo (114570).
• Genital herpes. It is unclear if oral echinacea is beneficial for genital herpes in patients with herpes simplex virus (HSV) type 1 or 2. Details: Some clinical research shows that a specific E. purpurea extract (Echinaforce, A. Vogel Bioforce AG) 800 mg orally twice daily for 6 months does not seem to prevent or reduce the frequency or duration of recurrent genital herpes in patients with herpes simplex virus (HSV) type 1 or 2 (7087).
• Gingivitis. Echinacea, in a mouth rinse or periodontal patch, has only been studied in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that using a mouth rinse containing echinacea, gotu kola, and elderberry (HM-302, Izun Pharmaceuticals) 15 mL three times daily for 14 days might prevent worsening of gingivitis when compared with a placebo rinse, but it produces only minimal improvement in symptoms (20069). Applying a periodontal patch containing echinacea, gotu kola, and elderberry (PerioPatch, Izun Pharmaceuticals) either as a single dose, or three times daily for 1 day then once daily for 2 days seems to reduce some measures of inflammation and gingivitis at some time points, but effects lack consistency (20068,20070).
• Herpes labialis (cold sores). Although there has been interest in using topical echinacea for herpes labialis, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• HIV/AIDS. Although there has been interest in using oral echinacea for HIV/AIDS, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• Human papillomavirus (HPV). Oral echinacea has only been studied in combination with other ingredients; its benefit when used alone is unclear. Details: Preliminary clinical research shows that taking a specific combination product containing echinacea, andrographis, grapefruit, papaya, pau d'arco, and cat's claw (Immune Act, Erba Vita SpA) three tablets daily for one month reduces the recurrence of anal condylomata in patients following surgical removal. After one month, the recurrence rate was about 4% in the echinacea group compared with 18% in the control group; after 6 months the recurrence rates were about 7% and 27%, respectively (20073). However, poor study methodology limits the validity of these findings.
• Influenza. Limited data suggest that oral echinacea may improve the response to influenza vaccine, and that a combination product containing echinacea may improve rates of recovery from influenza. Details: Preliminary clinical research shows that a taking a specific echinacea product (Monoselect Echinacea, PharmExtracta) 200 mg orally daily for 15 days, then 100 mg daily for 15 days, followed by 100 mg every other day for 60 days, might improve the response to influenza vaccine in people with chronic bronchitis or asthma (18226). Higher quality research is needed to confirm these results. Taking a specific combination product (Echinaforce Hot Drink, A. Vogel Bioforce AG), containing elderberry juice and extracts of E. purpurea above-ground parts and roots, 5 mL five times daily for 3 days, then three times daily for 7 days, improves rates of recovery and influenza-related respiratory complications similarly to oseltamivir 75 mg twice daily for 5 days (95650). However, due to the lack of a placebo group, it is unclear if both treatments were beneficial or if the outcomes represent the natural progression of influenza.
• Insect bite. It is unclear if topical homeopathy with a gel containing echinacea is beneficial for insect bite treatment. Oral echinacea has not been evaluated for this use. Details: Preliminary clinical research shows that using a homeopathic after-bite gel, containing echinacea, marsh Labrador tea, and stinging nettle, on affected areas does not reduce erythema or itching after a mosquito bite when compared with placebo (89235).
• Lichen planus. It is unclear if oral echinacea is beneficial for patients with this condition. Details: A small clinical study in adults with erosive oral lichen planus in Iran shows that taking a specific echinacea extract tablet (Immustim, Goldaru Corp.) 114 mg three times daily for 35 days decreases pain scores, number of lesions, and symptom severity when compared with placebo. However, all patients also used a mouthwash containing betamethasone, diphenhydramine, nystatin, and aluminum-magnesium suspension three times daily (111173).
• Malaria. Although there has been interest in using oral echinacea for malaria, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• Migraine headache. Although there has been interest in using oral echinacea for migraine headache, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• Otitis media. Oral echinacea does not seem to reduce the rate of recurrence of otitis media in young children, and may actually increase it. Details: Preliminary clinical research shows that taking a specific liquid extract of echinacea fresh roots and dried mature seeds, 0.5 mL three times daily for 3 days at the first sign of a common cold, followed by 0.25 mL three times daily for 7 days, does not prevent otitis media in children 1-5 years of age with a history of recurrent otitis media. In fact, the risk of an episode of otitis media during the 6 month follow-up seemed to increase by 59% in those taking echinacea when compared with placebo (20063).
• Psoriasis. Although there has been interest in using topical echinacea for psoriasis, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• Respiratory tract infections. It is unclear if oral echinacea is beneficial for preventing or treating respiratory tract infections. Details: A large clinical study in adults with respiratory tract infections shows that using echinacea spray or taking echinacea lozenges 16,800 mg daily during days 1-3 and 2240-3360 mg daily afterward for up to 10 days does not improve time to recovery, symptom relief, or number of sick days when compared with echinacea tablets or drops at a prophylactic dose of 2400 mg daily for 10 days. However, the higher dose from days 1-3 is associated with faster viral clearance than the prophylactic dose (111540). The validity of these effects is limited by insufficient blinding and a lack of a placebo group. Additionally, echinacea has been studied for prevention of respiratory tract infections. A meta-analysis of many clinical trials shows that taking echinacea up to 16,800 mg daily, alone or in combination with other products, for up to 17 weeks reduces the risk of respiratory infection and antibiotic prescriptions when compared with control (114568). The validity of this study is limited by heterogenous methods between clinical trials, including population, dose, and outcome definitions and measurements.
• Rheumatoid arthritis (RA). Although there has been interest in using oral echinacea for RA, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• Tonsillitis. Oral echinacea has been used with azithromycin to reduce relapses of recurrent tonsillitis in children. A throat spray containing echinacea has also been evaluated for tonsillitis-associated sore throat. It is unclear if echinacea is beneficial for either purpose. Details: Preliminary clinical research in children with recurrent tonsillitis shows that adding echinacea suspension, 250 mg root powder per 5 mL, orally 3 times daily for 10 consecutive days per month for 6 months, to azithromycin 10 mg/kg/day for 6 consecutive days per month for 6 months reduces the number of tonsillitis attacks when compared with azithromycin alone (104127). However, the study was not blinded and the number of tonsillitis episodes in both groups was very low. Other preliminary clinical research shows that applying a throat spray containing sage and echinacea whole plant extract every 2 hours up to 10 times daily for up to 5 consecutive days is as effective as a chlorhexidine-lidocaine spray in patients with sore throat due to acute pharyngitis or tonsillitis (20077).
• Tonsillopharyngitis. Oral echinacea has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized study in patients aged 12-75 years with acute tonsillopharyngitis shows that taking lozenges containing echinacea extract 800 mg and sage extract 5 times daily for 4 days reduces throat pain and tonsillopharyngitis symptoms when compared to baseline, both acutely within 90 minutes and after 4 days of treatment (111530). The validity of these effects is limited by a lack of a comparator group. It is unclear if these effects are due to echinacea, sage, or the combination.
• Upper respiratory tract infection (URTI). It is unclear if oral echinacea is beneficial for preventing or treating URTIs. Details: A moderate-size open-label clinical study tested the effects of echinacea to prevent or treat respiratory viruses. This study of otherwise healthy adults in Bulgaria shows that taking echinacea extract (Echinaforce, A. Vogel AG) 2400 mg daily for cycles of 2, 2, and 1 months, with a 1-week break between each cycle, does not reduce symptomatic respiratory tract infections, including SARS-CoV-2, or respiratory virus detection overall when compared with usual care. However, echinacea extract does reduce the risk of a positive test for coronaviruses or SARS-CoV-2 by 48% and 63%, respectively. In patients who develop a symptomatic respiratory tract infection, this study also shows that taking the same echinacea extract 4000 mg daily for up to 10 days speeds viral clearance compared with usual care when all virus types were analyzed; however, clearance of SARS-CoV-2 was not improved. Echinacea may also reduce the number of days with a fever, but not other symptoms (111174). The validity of this study is limited by lack of blinding. Further, most patients were unvaccinated against COVID-19; it is unclear whether these results can be extrapolated to vaccinated patients. Another large study in adults with URTIs shows that taking a combination product containing echinacea 1100-2200 mg, zinc, and vitamin C (EZC Pak) daily for 5 days reduces time to recovery by 1.4 days but does not reduce symptom severity when compared with placebo (111512). The validity of these effects is severely limited by multiple instances of selection bias. Additionally, it is unclear if these effects are due to echinacea, other ingredients, or the combination.
• Urinary tract infections (UTIs). Although there has been interest in using oral echinacea for UTIs, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• Vaginal candidiasis. Although there has been interest in using oral echinacea for vaginal candidiasis, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• Warts. It is unclear if oral echinacea is beneficial for warts when used alone or in combination with other ingredients. Details: Preliminary clinical research shows that taking echinacea 600 mg orally once daily for up to 3 months does not clear common, plantar, or plain cutaneous warts any more effectively than placebo (20080). Other preliminary clinical research shows that taking an oral supplement containing echinacea with methionine, zinc, probiotics, antioxidants and immunostimulants for 6 months, in addition to using conventional topical therapy to treat cutaneous warts, seems to increase the rate of complete remission from 54% to 86% when compared with conventional therapy alone (20071). It is unclear if these effects are due to echinacea, other ingredients, or the combination.
• Water warts. It is unclear if oral echinacea is beneficial for water warts (molluscum contagiosum). Details: In children who have been successfully treated with curettage for molluscum contagiosum, taking a combination of E. angustifolia and E. purpurea orally daily for 2 months is associated with a relapse rate of about 39%, compared with a rate of 68% in a control group that received no oral treatment (104128). The validity of this finding is limited by the lack of a placebo control. E. angustifolia and E. purpurea were taken in doses of 200 mg each in children under 20 kg and 400 mg each in children over 20 kg. More evidence is needed to rate echinacea for these uses.

(Read more about ECHINACEA)

EFFECTIVE

• Folate deficiency. Oral or intravenous folic acid is effective for the prevention or treatment of folate deficiency. Details: Administering folic acid orally or parenterally improves and prevents folate deficiency (505,8739). Clinical research shows that supplementation with folic acid 100 mcg to 5 mg daily during pregnancy decreases the risk of developing megaloblastic anemia by up to 79% (91307).

LIKELY EFFECTIVE

• Kidney failure. Taking folic acid orally reduces homocysteine levels in people with kidney failure who are on hemodialysis. Details: Over 85% of people with kidney failure have hyperhomocysteinemia. Treatment of hyperhomocysteinemia in kidney failure is often more difficult than with normal kidney function (1489,3324,7289,9413,9414,9416). The reasons for this are not fully understood; renal uptake and metabolism of homocysteine may be reduced in severe kidney failure, and hemodialysis may contribute to vitamin deficiencies (6884,9414,9417). Folic acid 0.8-15 mg daily or 3 times weekly is generally used, but the degree of homocysteine reduction varies between 12% to 50%, and normal homocysteine levels (less than 12 µmol/L) cannot always be achieved. Adding vitamin B12 400-1000 mcg daily and vitamin B6 20-50 mg daily produces an additional reduction in homocysteine (1489,6884,7289,7881,9322,9413,9414,9415,9416,9417). Folic acid doses greater than 15 mg daily do not seem to provide additional benefit. Also, doses of 30-60 mg might cause a rebound in homocysteine levels when treatment is stopped (9219). Despite the homocysteine-lowering effect of folic acid in kidney failure, the most robust meta-analysis of 11 clinical trials suggests that folic acid supplementation does not seem to reduce the risk of cardiovascular events (50527). A smaller meta-analysis of 7 clinical trials that used a different primary composite outcome suggests that folic acid might reduce the risk of cardiovascular events by 15% when compared with control (91311). There has also been interest in using a reduced form of folic acid, L-5-methyltetrahydrofolate (L-5-MTHF). One study in patients on hemodialysis suggests that taking L-5-MTHF 17 mg daily for 12 weeks might lower homocysteine levels to a greater extent than an equimolar 15 mg of folic acid (104908). Another clinical trial in patients on hemodialysis suggests that giving intravenous L-5-MTHF 50 mg three times weekly is associated with an increased survival of about 36 months, compared with about 26 months with folic acid 5 mg daily. There was no difference in homocysteine reduction between groups (104909). These results should be interpreted with caution because they have not been replicated, and there was no placebo control. Furthermore, survival may have been affected by the availability of kidney transplants.
• Hyperhomocysteinemia. Oral folic acid, taken alone or in combination with other B vitamins, lowers homocysteine levels in most patients. However, it is unclear if this has cardiovascular benefits. Details: Taking folic acid orally 0.4-5 mg daily lowers fasting homocysteine levels by 20% to 30% in people with normal to moderately elevated homocysteine levels at baseline. Folic acid 0.8-1 mg daily seems to provide maximal reduction (9307,9400,9401,9405,9408,11337,11338,50145). Doses above 1 mg daily do not seem to add benefit (9307), except in some people with certain gene mutations that cause homocysteine levels of 20 µmol/L or higher (9408). The higher the initial homocysteine levels, the lower the folic acid dose needed to attain maximum homocysteine reduction (9307). The effects of folic acid supplementation on homocysteine concentrations appear to be greater in females than males (50145). Adding vitamin B6 25-250 mg or vitamin B12 500 mcg seems to further reduce homocysteine levels (1489,9400,9405,9406,9408,107136). Some experts recommend routine use of vitamin B12 in homocysteine-lowering regimens to avoid the risk of neuropathy in people with undetected vitamin B12 deficiency (9405). Increasing folic acid intake with supplements or folate-fortified cereal products is more effective for reducing homocysteine levels than increasing intake of folate-rich foods (6367). Fortification of cereals and flour with 140 mcg folic acid per 100 grams reduces the mean homocysteine level in the general population by about 7% (7881,9404,9407). Elevated homocysteine levels are considered by some to be an independent risk factor for atherosclerosis progression, recurrent thromboembolism, deep vein thrombosis, myocardial infarction, ischemic stroke, and other vascular complications (3886,3887,6236,7725,9314,9318,50509). However, elevated homocysteine levels may be a marker, as opposed to a cause, of vascular disease (11387,11388). Although folic acid lowers homocysteine levels, it is not yet known whether this reduces the risk of vascular disease. One meta-analysis shows that taking folic acid can reduce the risk of stroke by about 10% in patients with cardiovascular disease (CVD); the reduction is greatest in patients for whom homocysteine levels are lowered by at least 25% (96157). A meta-analysis of 10 clinical trials, including over 44,000 patients at risk for or with a history of CVD, shows that B vitamin supplementation reduces the relative risk of stroke by 10% when compared with placebo (97619). Also, a meta-analysis in patients with a history of stroke shows that B vitamin supplementation, including folic acid, reduces the relative risk of stroke recurrence by 13% and the risk of vascular death by 11% when compared with placebo (107136). However other research does not agree. Meta-analyses of clinical research show that folic acid does not prevent CVD or coronary heart disease, in spite of lowering homocysteine by up to 55%, when individuals with normal or high levels of homocysteine are considered (50539,96147,97619). Furthermore, most research shows that folic acid supplementation, alone or in combination with vitamin B6 and vitamin B12, does not improve endothelial function or improve secondary prevention of cardiovascular events such as myocardial infarction in people with existing CVD despite a homocysteine-lowering effect (9313,11337,11387,13482,50437,97619). Some research even suggests an increase in CVD risk concurrent with homocysteine lowering (13482). Large randomized controlled trials are needed to confirm or refute these findings. Some researchers hypothesize that different genetic profiles might explain some of these conflicting results. For instance, individuals with a homozygous 677TT MTHFR genotype typically have increased homocysteine levels. However, a meta-analysis suggests that treatment with folic acid does not reduce the risk of ischemic heart disease despite reducing homocysteine levels in individuals with 677TT MTHFR (50456). It has also been theorized that a reduced form of folic acid, 5-methyltetrahydrofolate (5-MTHF) might work better in these individuals. Although [6RS]-5-MTHF has been shown to lower homocysteine levels (104915), studies assessing its cardiovascular benefits are lacking.
• Methotrexate toxicity. Oral folic acid reduces the severity of methotrexate toxicity. Details: Oral folic acid reduces methotrexate toxicity symptoms, such as nausea and vomiting, in the treatment of rheumatoid arthritis (RA) and psoriasis (768,2162,2163,2164,4492,4493,4494,9369,9419). Folic acid also seems to reduce methotrexate-induced hepatic side effects by approximately 36% (50320). Some research shows that a low, 0.8 mg weekly dose of folic acid is equally effective to a higher dose of 5 mg weekly for the prevention of methotrexate toxicity (102388).
• Neural tube birth defects. Oral folic acid helps to prevent neural tube birth defects in newborns. Details: Clinical practice guidelines recommend that anyone capable of becoming pregnant take folic acid 400 mcg daily from fortified foods or supplements to prevent neural tube birth defects in infants. Folic acid 600 mcg daily is advised during pregnancy (94811,96146). This recommendation is based on research showing that a higher intake of folic acid from food and supplements during pregnancy reduces the primary incidence of neural tube birth defects by 41% to 69% (3325,9309,50344,50403,50468,95156). Individuals with a history of children with neural tube birth defects usually take a higher dose of folic acid 4000 mcg daily starting one month before and continuing for up to 3 months after conception (96146). Evidence shows that, when used for secondary prevention, folic acid supplementation reduces the incidence of neural tube defects by 66% to 87% (21235,50263,50344,50403,95156). In the US, foods containing at least 60 mcg of folic acid can be labeled with a health claim stating that healthful diets with adequate folic acid intake may reduce the risk of having a child with a brain or spinal cord defect (102369).

POSSIBLY EFFECTIVE

• Cognitive impairment. Taking folic acid alone, with other B vitamins or with docosahexaenoic acid (DHA), might improve thinking and memory skills in older patients with cognitive impairment. Details: One clinical trial in patients aged 65 years and older with mild cognitive impairment (MCI) shows that taking folic acid 400 mcg daily for 2 years increases IQ scores when compared with placebo (100952). Two small, low-quality clinical studies in patients aged 70-90 years with cognitive impairment and low folate levels or folate deficiency shows that taking folic acid 5 or 15 mg daily for up to 63 days improves cognitive function, including measures such as memory and attention, when compared with placebo or baseline (50301,104911). Folic acid also appears to be beneficial when used in combination with other B vitamins or with DHA. A clinical trial in patients aged 70 years and older with MCI shows that taking folic acid 800 mcg, vitamin B6 20 mg, and vitamin B12 500 mcg daily for 2 years mitigates decline in executive function and, in patients with high baseline homocysteine levels, improves cognition and memory when compared with placebo (50480). Taking folic acid 800 mcg with or without DHA 800 mg daily for 6 months modestly improves cognition, as measured on the full-scale intelligence quotient, when compared with placebo (103978,109196). However, this benefit is no longer present at 6 months after treatment discontinuation (109196).
• Depression. Oral folic acid seems to modestly reduce depression severity when added to conventional antidepressant therapy. It is unclear if folic acid can reduce the prevalence of depression or the risk for suicide. Details: Observational studies suggest that depression is correlated with low folate status, particularly in females (50105,50127,50243). Taking folic acid 0.2-15 mg daily for up to 6 months with conventional antidepressants seems to improve treatment response in patients with major depressive disorder (3657,10884,10887,50566,109190). One meta-analysis shows that taking L-methylfolate or folic acid as an adjunct to treatment with conventional antidepressants modestly reduces depression severity when compared with placebo and conventional antidepressants. The response and remission rates were improved by 36% and 39%, respectively (109190). However, limited clinical research suggests that folic acid is not effective as a replacement for conventional antidepressant therapy (10886). Also, a small clinical study in adolescents at high familial risk for mood disorders suggests that taking folic acid 2.5 mg daily for up to 36 months does not prevent mood disorders when compared with placebo. However, in the patients that were eventually diagnosed with depression, the time of onset was delayed from 5 months to 15.5 months in the group using folic acid when compared with placebo (91313). Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that folic acid is not currently recommended as monotherapy treatment for unipolar depression (110318). Observational research has also evaluated the association between folic acid supplementation and suicidal events in patients with or without depression. One within-person cohort study, in which only 12% of patients were diagnosed with depression, has found that filling a folic acid prescription of 0.4-5 mg daily, either alone or as part of a multivitamin, is associated with a reduced risk for suicidal events during the following months when compared with months without a prescription (109201). It is unclear what percentage of these patients, if any, had folate deficiency at baseline.
• Hypertension. Oral folic acid seems to modestly reduce hypertension. Details: A meta-analysis of clinical research shows that taking folic acid 5-10 mg daily for at least 6 weeks reduces systolic blood pressure by 2mmHg and improves flow-mediated dilation by 1.6% in hypertensive individuals (50364). Some research has evaluated folic acid in hypertensive patients when used with antihypertensive drugs. Results show that taking folic acid 400-800 mcg in combination with enalapril 10 mg daily for about 4.5 years does not improve blood pressure when compared with enalapril alone (50302,96158). However, in hypertensive patients with heavy proteinuria, this combination seems to reduce the risk of all-cause mortality by about 41% when compared with enalapril alone (96158).
• Phenytoin-induced gingival hyperplasia. Topical folic acid seems to reduce gingival hyperplasia due to phenytoin. The effect of oral folic acid is unclear. Details: Applying folic acid topically seems to inhibit gingival hyperplasia secondary to phenytoin therapy (2151). However, taking folic acid orally does not seem to improve gingival hyperplasia secondary to phenytoin therapy in adults (2150,2151,2152), although some evidence suggests that taking folic acid 500 mcg daily reduces the risk of phenytoin-induced gingival hyperplasia by 33% in children when compared with placebo (50463).
• Stroke. Although some clinical research has shown that oral folate reduces stroke risk by a small amount, more research is needed to determine who is most likely to benefit. Most individual clinical trials show that folic acid seems to reduce stroke risk only in regions without food-fortification policies. Details: Multiple clinical studies have shown that folic acid supplementation reduces the risk of stroke by 10% to 25% in regions WITHOUT established policies mandating folic acid fortification of grain products (50240,50485,50525,50539,91325,96154,96157,96159,97308). The effect appears to be greatest when folic acid is taken in low doses (usually 0.8 mg daily or lower) (50525,96157,96159), in regions with a low prevalence of statin use (50525,96159), in patients with high cholesterol levels at baseline (96152), in patients who achieve homocysteine reduction of at least 20% (50407,96157), and in patients with the lowest folate levels at baseline (96154,96157). There is also some evidence that the effect of folic acid on stroke risk is greatest in patients with low baseline levels of vitamin B12 (96159). In 2001, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Most research shows that folic acid supplementation does not reduce the risk of stroke in regions WITH established policies mandating folic acid fortification (50240,50485,50525,50539,96157,96159,97308). However, there is some evidence that folic acid may reduce the risk of stroke in patients from regions with folic acid fortification who have recently had a stroke or transient ischemic attack and are not using antiplatelet drugs (90379). Meta-analyses of clinical research have been conducted. However, possible confounding due to the presence or absence of folic acid fortification is unclear. A meta-analysis of the available research in adults with existing CVD shows that folic acid supplementation at a daily dose of less than 2 mg reduces the risk for stroke by about 10% (102386). Also, a meta-analysis of 10 clinical trials, including over 44,000 patients at risk for or with a history of CVD, shows that B vitamin supplementation, including folic acid, reduces the relative risk of stroke by 10% when compared with placebo (97619). In patients with a history of stroke, a meta-analysis shows that B vitamin supplementation reduces the relative risk of stroke recurrence by 13% and the risk of vascular death by 11% when compared with placebo (107136). It is unclear if folic acid reduces the stroke risk in patients with impaired kidney function. Some research shows that taking folic acid in combination with high doses of vitamin B12 (cyanocobalamin) does not reduce the risk of stroke in these patients (11387,96150). However, there is concern that the lack of benefit may have been due to the decline in kidney function from high doses of cyanocobalamin (96150). Additional research is needed to determine if folic acid supplementation is beneficial in patients with impaired kidney function when used with other forms of vitamin B12 such as methylcobalamin or hydroxycobalamin.
• Vitiligo. Oral folic acid seems to improve vitiligo symptoms. Details: Taking folic acid orally seems to improve symptoms of vitiligo (2153,2154). This finding is supported by a meta-analysis of observational research which shows that patients with vitiligo have higher serum homocysteine levels when compared with patients without vitiligo (100951).

POSSIBLY INEFFECTIVE

• Anemia. Adding oral folic acid to oral iron therapy does not seem to improve hematologic parameters in patients with anemia. Details: In postpartum patients with anemia, clinical research shows that taking iron as ferrous fumarate 600 mg and folic acid 1 mg daily is no more effective than iron alone for improving hemoglobin status (91319). Also, clinical research in non-pregnant menstruating females shows that taking folic acid 0.4 mg daily or 2.8 mg once weekly for 16 weeks with iron 60 mg daily does not reduce anemia or improve iron status when compared with iron alone (109193). During pregnancy, clinical research shows that folic acid supplementation does not decrease the risk of pre-delivery anemia or low hemoglobin levels (91307).
• Age-related cognitive decline. Oral folic acid does not seem to prevent cognitive decline in healthy elderly adults. Details: Most clinical research shows that taking folic acid, alone or in combination with other B vitamins, does not improve cognitive function, including memory, language, or executive function, in elderly adults with age-related cognitive decline (50318,50412,50510). In fact, a large-scale observational study in the US has found that people over 65 years of age who consume large amounts of folic acid (median of 742 mcg daily) have cognitive decline at a rate twice as fast as those consuming smaller amounts (median of 186 mcg daily) (13068). While most research on folic acid for age-related cognitive decline lacks positive findings, many of the studies are small, short-term (<1 year), underpowered to detect significant differences, and not specific to patients with high homocysteine levels. Population research has found that high homocysteine levels are associated with decreased cognition in older adults, suggesting that using folic acid to lower homocysteine levels might mitigate cognitive decline in these patients (50094). Two long-term clinical trials examining the effects of folic acid in elderly adults with high homocysteine levels show mixed results. A large-scale clinical trial of patients aged 50-70 years from the Netherlands who have high homocysteine levels shows that taking folic acid 800 mcg daily for 3 years increases memory, information processing, and other measures of cognitive function when compared with placebo (15271). However, another large-scale clinical trial of patients aged 65 years and older from the Netherlands who have high homocysteine levels shows that taking folic acid 400 mcg and vitamin B12 500 mcg daily for 2 years lowers homocysteine levels, but does not appear to improve overall measures of cognitive function, when compared with placebo (90392). The reasons for the discrepant findings in these two studies are not clear but might relate to differences in the dose of folic acid, duration of treatment, and age of patients included.
• Cataracts. Oral folic acid does not seem to reduce cataract development. Details: Clinical research in females with existing cardiovascular disease (CVD) or with risk factors for CVD shows that taking folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg daily for an average of 7.3 years does not reduce the risk of developing cataracts. Furthermore, the risk of cataract extraction was increased by 28% in these patients (96149).
• Diarrhea. Oral folic acid does not seem to reduce the risk of diarrhea, and might even increase the incidence of diarrhea in children. Details: In children aged 6-30 months at risk of malnourishment, clinical research shows that taking a nutritional supplement (Nutriset Ltd) enriched in folic acid 75-150 mcg, with or without vitamin B12 0.9-1.8 mcg, daily for 6 months does not reduce the incidence of diarrhea when compared with placebo. Enrichment with folic acid, with or without vitamin B12, actually seems to increase the likelihood of having more episodes of both persistent diarrhea and diarrhea lasting over 3 days (90391).
• Fall prevention. Oral folic acid does not seem to reduce the risk of falls. Details: Clinical research shows that taking a combination of B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg daily, for 2 years, does not prevent falls when compared with placebo in elderly individuals also taking vitamin D (96148).
• Fetal and premature infant mortality. Oral vitamin B12 does not seem prevent mortality in premature infants. Details: Clinical research shows that supplementation with folic acid during pregnancy does not decrease the risk of miscarriage, stillbirth, or neonatal death (91307,96156).
• Leukemia. Oral vitamin B12 does not seem to reduce the risk for pediatric acute lymphoblastic leukemia. Details: A meta-analysis of results from two case-control studies has found that increased folate intake during pregnancy is not associated with a reduced risk of childhood acute lymphoblastic leukemia (50247).
• Male infertility. Oral folic acid does not seem to improve sperm parameters or pregnancy rates in males with infertility. Details: Some small clinical studies show that taking folic acid, alone or with zinc, increases sperm count in males with idiopathic infertility or in males with a grade III varicocele (9334,90194). However, another small study in males with asthenozoospermia shows that taking folic acid 5 mg, selenium 200 mcg, and vitamin E 400 IU daily for 3 months does not improve sperm parameters when compared with placebo (104907). Furthermore, there seems to be no improvement in clinical outcomes. One large, high-quality clinical study in males with idiopathic infertility shows that taking folic acid 5 mg with zinc 30 mg daily for 6 months does not improve sperm morphology, pregnancy rate, or live birth rate when compared with placebo (102085). Folic acid has also been evaluated in combination with other ingredients. A retrospective study in males with or without varicocele-related infertility suggests that taking a specific combination product containing folic acid 0.2 mg, vitamin C, zinc, L-carnitine fumarate, acetyl-L-carnitine, coenzyme Q10, selenium, and vitamin B12 (Proxeed Plus, Sigma-Tau) twice daily for 6 months is associated with improvements in sperm count, sperm concentration, and sperm motility when compared to baseline. Improvement in semen parameters were greatest in subjects with more severe varicoceles (111296). The validity of this study is limited by the lack of a comparator group.
• Osteoporosis. Oral folic acid does not seem to reduce the risk of osteoporotic fractures. Details: Clinical research in elderly adults or adults with a history of cerebrovascular disease shows that taking vitamin B12 500 mcg and folic acid 0.4-2 mg, with or without vitamin B6 25 mg, daily for 2-3 years does not seem to reduce the risk for osteoporotic fractures when compared with placebo (90377,90393). A 5-7 year follow-up of this research has also found no benefit (103981).
• Physical performance. Oral folic acid does not seem to improve physical performance in older adults. Details: Clinical research shows that taking a combination of B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg daily for 2 years, does not improve hand strength or improve performance such as walking when compared with placebo in elderly individuals also taking vitamin D (96148).
• Pre-eclampsia. Oral folic acid does not seem to prevent pre-eclampsia in pregnant patients. Details: While the effect of low-dose prenatal folic acid is unclear, high-dose folic acid does not seem to reduce the risk of pre-eclampsia. Some population research has found that low-dose folic acid is associated with a 22% reduced odds of pre-eclampsia, while other research has found no association (91308,99370,99372,110447). A large clinical trial evaluating high-dose folic acid in pregnancies at risk for pre-eclampsia shows that taking 4 mg daily, starting at 8-16 weeks of gestation and continuing until delivery, does not reduce the risk of pre-eclampsia when compared with placebo (103929). A secondary analysis of this study in twin pregnancies has also found no benefit with high-dose folic acid supplementation (103977).
• Respiratory tract infections. Oral folic acid does not seem to prevent respiratory tract infections. Details: Clinical research in children aged 6-30 months at risk of malnourishment shows that taking a nutritional supplement (Nutriset Ltd) enriched in folic acid 75-150 mcg, with or without vitamin B12 0.9-1.8 mcg, daily for 6 months does not reduce the incidence of lower respiratory infections when compared with a supplement not enriched with folic acid and vitamin B12 (90391).

LIKELY INEFFECTIVE

• Colorectal adenoma. Oral folic acid does not prevent colorectal adenomas. Details: Although some population research and one clinical study has found that high folate intake is associated with reduced colorectal adenoma risk (2142,2143,91303), most clinical research does not support this finding. Clinical research shows that taking a combination of B vitamins, including folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg daily for up to 9.2 years, does not reduce the risk of colorectal adenoma in females at high risk of cardiovascular disease when compared with placebo (90389). Other clinical research suggests that taking folic acid does not reduce the occurrence or recurrence of adenomas or incidence of advanced adenomas (34596,50241,50265,50369,50394,50449,50522). Furthermore, treatment with folic acid for more than 3 years seems to be associated with an increased risk of advanced adenomatous lesions (50378).
• Fragile X syndrome. Oral folic acid does not improve symptoms in children with fragile X syndrome. Details: Clinical research shows that taking folic acid orally does not improve symptoms of fragile X syndrome (2155,2156,2157,2158,2159,2160,50575).
• Preterm labor. Oral folic acid does not seem to reduce the risk of preterm birth. Details: Meta-analyses of clinical research show that supplementation with folic acid 200 mcg to 5 mg during pregnancy does not decrease the risk of preterm birth (91307,96155). An observational study in patients with and without epilepsy found that folic acid supplementation during pregnancy was associated with a lower odds of preterm birth in patients receiving antiseizure medications; however, no link between folic acid and preterm labor was reported in patients without epilepsy or in those with epilepsy not receiving antiseizure medications (110447).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Abdominal wall defects. It is unclear if oral folic acid helps to prevent abdominal wall defects in newborns. Details: Observational research in a population in northern China has found that taking folic acid supplements until the end of the first trimester modestly reduces the risk of abdominal wall defects and the risk of omphalocele, specifically, in the newborn when compared with not taking folic acid. However, this association was not found in a population in southern China (109191). These differing outcomes may be related to the lower dietary folate intakes in northern China.
• Acne. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults and children with inflammatory acne shows that taking 1-4 tablets of a specific product (NicAzel, Elorac Inc.) containing folic acid, vitamin B6, nicotinamide, azelaic acid, zinc, and copper for 8 weeks reduces inflammatory lesions and improves appearance in 88% and 81% of patients, respectively, when compared with baseline (90800).
• Age-related macular degeneration (AMD). Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large-scale clinical study shows that taking folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg daily reduces the risk of developing AMD in females over 40 years of age with a history of cardiovascular disease (CVD) or with risk factors for CVD. Those who took this combination for an average of 7.3 years had a 34% reduced risk of developing AMD and a 41% reduced risk of visually significant AMD when compared with placebo (14620). It is unclear if this effect is due to folic acid, other ingredients, or the combination.
• Age-related testosterone deficiency. Folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in males with overweight or obesity, mild erectile dysfunction, and normal to low androgen levels shows that taking a combination product containing folic acid 400 mcg, alpha-lipoic acid, myo-inositol, and apple (Sinopol Forte) increases testosterone, luteinizing hormone, and measures of erectile dysfunction but not follicle-stimulating hormone or sperm parameters when compared to baseline (111674). The validity of these effects is limited by the small sample size and the lack of a comparator group, and it is unclear if these effects are due to folic acid, other ingredients, or the combination.
• Alzheimer disease. It is unclear if oral folic acid reduces the risk of developing this condition. Details: Low levels of folate and high levels of homocysteine have been linked to a greater risk of Alzheimer disease (50094). Also, some observational studies have found that higher intake of folate from the diet and supplements in elderly adults is associated with a reduced risk of developing Alzheimer disease when compared with lower intake (13165,15270). One small clinical trial in patients with Alzheimer disease who are taking cholinesterase inhibitors shows that taking folic acid 1 mg daily for 6 months increases the likelihood of treatment response, classified as global improvement in behavioral and/or functional status with no decline in mental status scores, by 78% to 87% when compared with placebo (50246). Also, preliminary clinical research in patients with probable Alzheimer disease who are not consuming a folate-fortified diet shows that taking vitamin B12 50 mcg daily plus folic acid 1.2 mg daily for 6 months modestly improves some measures of cognitive performance and decreases levels of homocysteine when compared with placebo (107150). However, not all research agrees. Clinical research in patients with probable Alzheimer disease using routine medications shows that taking folic acid 5 mg, vitamin B12 1 mg, and vitamin B6 25 mg daily for 18 months does not have a beneficial effect on cognitive function or the severity of disease when compared with placebo (50319). However, all patients in this study were also consuming a folate-fortified diet.
• Angioplasty. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some evidence suggests that folic acid 1 mg, vitamin B12 400 mcg, and pyridoxine 10 mg daily can decrease the rate of restenosis in patients treated with balloon angioplasty (8009,9412). However, this combination does not seem to be as effective for reducing restenosis in patients after coronary stenting (8009). An intravenous loading dose of folic acid, vitamin B6, and vitamin B12 followed by oral administration of folic acid 1.2 mg, vitamin B6 48 mg, and vitamin B12 60 mcg daily after bare metal coronary stenting also does not seem to reduce restenosis and might actually increase restenosis (12150,12151). Due to the lack of evidence of benefit and potential for harm, this combination of vitamins should not be recommended for patients receiving coronary stents (12151).
• Atopic dermatitis (eczema). It is unclear if oral folic acid during pregnancy reduces the risk of eczema in the child. Details: Observational research has found that consuming both iron and folic acid supplements during pregnancy is associated with a four-fold reduced risk for developing atopic dermatitis in the child. However, use of either iron or folic acid supplementation alone is not associated with an effect on the child's risk for atopic dermatitis (102387).
• Autism spectrum disorder. It is unclear if oral folic acid intake during pregnancy reduces the risk of autism spectrum disorder in the child. Details: A meta-analysis of population research has found that consumption of folic acid of at least 400 mcg daily from both diet and supplements during pregnancy is associated with a 45% reduced risk of autism in the child at 2-15 years of age. Also, supplementation with folic acid during the prenatal to early period of pregnancy is associated with an approximate 43% reduced risk of autism in the child. This association did not differ between countries with or without a folate fortification program (109198). An individual population study has also found that prenatal folic acid supplementation initiated the first day of the last menstrual period before conception is associated with a 39% reduced odds of autism in the child at age 3.3-10.2 years when compared to pregnancies without folic acid supplementation (91324).
• Beta-thalassemia. There is limited evidence on the oral use of folic acid for beta-thalassemia minor. Details: Patients with beta-thalassemia minor may experience decreased muscle strength and increased bone or muscle pain. A small clinical study in children with this condition shows that taking folic acid 1 mg, with or without L-carnitine 50 mg/kg, daily for 3 months reduces bone pain by 64% to 84% and increases the number of stairs climbed by 2- to 5-fold when compared with baseline (90631). The validity of this finding is limited by the lack of a control group.
• Bipolar disorder. It is unclear if adding oral folic acid to conventional bipolar therapy further improves symptoms. Details: Some clinical evidence suggests that folic acid does not improve the antidepressant effects of lithium in patients with bipolar disorder (50566). However, other clinical evidence suggests that taking folic acid in combination with valproate during the acute phase of mania improves the effects of valproate (50357).
• Breast cancer. It is unclear if oral folic acid reduces breast cancer risk. Details: Some older population research suggests that increased intake or levels of folic acid alone does not affect the risk of breast cancer or breast cancer-related mortality (50218,50224). However, in a specific group of women who also consume high amounts of dietary methionine, cyanocobalamin (vitamin B12), or pyridoxine (vitamin B6), dietary intake of folate is associated with a reduced risk of breast cancer (9328,50224). Also, more recent population research has found that folic acid plus folate dietary intakes between 153-400 mcg are associated with a reduced risk of breast cancer. This risk is further reduced in those who drink relatively large amounts of alcohol (90794). Folate intakes greater than 400 mcg daily do not appear to be protective against breast cancer (90794).
• Cancer. It is unclear if oral folic acid prevents cancer. Details: A large cohort study of children born to mothers with epilepsy on antiseizure medications suggests that prenatal folic acid exposure of 1 mg daily or more, at an average of 4.3 mg daily, is associated with a 2.7-fold greater risk of pediatric cancer when compared with children born to mothers with epilepsy but without prenatal exposure to high-dose folic acid. Additionally, this risk is not present in children of mothers without epilepsy taking high-dose folate (112103). It is unclear how maternal epilepsy, antiseizure medications, and folate interact to increase the risk of pediatric cancers. However, in the absence of clear guidelines, mothers with epilepsy should take no more than 4 mg of folic acid daily (112101,112102).
• Cardiovascular disease (CVD). Although oral folic acid does not seem to prevent most CVD events, some research suggests that increased dietary folic acid might lower the risk of stroke and CVD-related mortality in patients at high risk for CVD. Details: In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) approved a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Meta-analyses of available research show that folic acid might lower the risk of stroke in patients with CVD (97619,102386,107136). Some clinical research shows that taking folic acid reduces the risk of CVD by 15% in patients with kidney failure or chronic kidney disease (50444,91311). However, most research shows that folic acid supplementation, alone or in combination with vitamin B6 and vitamin B12, does not improve endothelial function or reduce the risk of death or CVD events in patients with existing hyperhomocysteinemia, coronary heart disease, CVD, kidney disease, or prior stroke, despite having a homocysteine-lowering effect (9313,9322,11337,11387,13482,50437) (50512,50527,96154,96147,97619,102386). Some population research has evaluated adults at high risk for CVD. This research has found that dietary folate intake of at least 382 mcg daily is associated with a modest reduction in CVD-related mortality and possibly all-cause mortality. Consuming folic acid as a component of fortified food in doses of more than 251 mcg daily is associated with a modest reduction in CVD-related mortality. Conversely, folic acid supplementation is associated with a higher risk of CVD and overall mortality, and there is a J-shaped association between folate intake, serum folate levels, and red blood cell folate levels, with both CVD-related and all-cause mortality (109199).
• Cervical cancer. It is unclear if oral folic acid prevents cervical cancer. Details: Epidemiological evidence has found that increasing folate intake from dietary and supplement sources, along with thiamine, riboflavin, and vitamin B12, might decrease the risk of precancerous cervical lesions (11074).
• Child development. It is unclear if oral folic acid supplementation during pregnancy improves child development. Details: Clinical research in Northern Ireland shows that taking folic acid 400 mcg daily starting in the 14th week of gestation and continuing until the end of pregnancy improves word reasoning in the child at 7 years of age when compared with placebo. When compared with a historical cohort from Britain, folic acid supplementation was associated with an increase in full scale IQ, verbal IQ, performance IQ, and general language at 7 years of age (102385). At age 11, benefits in word reasoning were no longer significant. However, there were modest benefits in some measures of processing speed when compared with placebo. Verbal comprehension was modestly improved in females, but not males (109192). Observational research in pregnant individuals and their children in Spain has found that taking less than 400 mcg of folic acid daily during pregnancy is associated with lower mental alertness scores in children at ages 7-9 years when compared with folic acid 400-999 mcg daily, while taking folic acid 1000 mcg or more daily during pregnancy was associated with improvements in some measures of working memory in the children. However, no relationship between folic acid dosing and most other measures of cognitive function was identified (110449).
• Chronic fatigue syndrome (CFS). Although there is interest in using oral or injectable folic acid for CFS, there is insufficient reliable information about the clinical effects of folic acid for this condition.
• Chronic kidney disease (CKD). While adding oral folic acid to enalapril might slow CKD progression, adding folic acid to high-dose vitamin B12 does not seem to be beneficial. Details: Clinical research in adults with hypertension and CKD shows that taking enalapril with folic acid 800 mcg for a median of 4.4 years reduces the risk of worsening kidney function by 21% and slows the rate of kidney function decline by 44% when compared with enalapril alone (96153). However, clinical research does not support the use of folic acid in patients with CKD when used in combination with high-dose vitamin B12 (cyanocobalamin). Vitamin B12 might increase the risk of negative outcomes (50253,50409,96150). More research is needed to determine the benefits of folic acid when used alone.
• Colorectal cancer. It is unclear if oral folic acid prevents colorectal cancer. Details: Although the majority of population research suggests that taking folic acid orally from dietary and supplemental sources reduces the risk of colorectal cancer (505,2140,2144,2145,2250,6271,9325,9326,50109,50427,50450)(91306,91323,96160,109188,110450), clinical evidence in general is not supportive. Most clinical research and meta-analyses of clinical trials suggest that taking folic acid from dietary or supplemental sources does not reduce the risk of colorectal cancer (2141,34596,50394). The reason for this discrepancy is unclear. Some observational research suggests that an inverse association between folate intake and risk of colorectal cancer was not apparent until at least 12 years after baseline folate intake was determined (109188). A meta-analysis of observational studies suggests that the benefits of folic acid supplementation on colorectal cancer risk might be limited to patients with moderate to high alcohol consumption (110450). Other clinical evidence suggests that the beneficial effect of folic acid may be limited to colon, but not rectal, cancer (21501). Furthermore, the beneficial effect for colon cancer may be limited to only certain subtypes. For instance, females with folate intake of at least 400 mcg daily seem to have a 46% reduction in the risk of p53-overexpressing colon cancer, but not p53-negative tumors, when compared with those who consume less than 200 mcg daily (21300). Also, the source of folic acid may influence its effects. Some observational research suggests that dietary folate, but not folic acid supplementation, reduces the risk of colon cancer (21501).
• Congenital heart disease. It is unclear if oral folic acid prevents congenital heart disease. Details: The exact cause of congenital heart disease is unknown but is thought to be a combination of genetic and environmental factors. Population research has found that supplementation with folic acid or folic acid-containing prenatal vitamins during pregnancy is associated with up to a 40% lower risk of congenital heart defects in newborns (99373).
• Dementia. It is unclear if oral folic acid is beneficial for the prevention or treatment of dementia. Details: While some preliminary research shows that folic acid might aid in the prevention and treatment of Alzheimer disease (13165,15270,50246,90374), two small clinical trials show that taking folic acid 15-20 mg daily for 10-12 weeks does not seem to improve cognitive function or the severity of dementia in patients with various forms of dementia, including vascular dementia, Lewy body dementia, probable Alzheimer disease, or dementia due to other causes (50062,50597).
• Diabetes. Small clinical studies suggest that oral folic acid does not improve glycemic control. Details: Meta-analyses of small clinical trials in patients with type 2 diabetes show that folic acid does not reduce glycated hemoglobin (HbA1C) when compared with placebo (50528,109197). Another small clinical study in patients with diabetes who are stabilized on metformin and/or a sulfonylurea shows that taking folic acid 5 mg daily for 8 weeks does not affect HbA1C when compared with placebo (104917). The validity of this study is limited by its small size and lack of blinding. Conversely, a meta-analysis of clinical research shows that taking folate modestly reduces fasting blood glucose and insulin levels, as well as measures of insulin resistance, when compared with placebo or no intervention (109197). There was no clear relationship between these changes and the dose or duration of folate. However, the studies included in this analysis evaluated multiple patient populations; the effect of folate in patients with diabetes, specifically, is unclear. Beyond glycemic control, some research has assessed the impact of dietary folate intake on cardiovascular risk in patients with diabetes. An observational study in Chinese adults with type 2 diabetes has found that dietary intake of folate in the highest quartile is associated with 68% lower odds of developing cardiovascular disease, defined as a non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina, when compared with folate intake in the lowest quartile (110452). Folic acid has also been evaluated in gestational diabetes. A meta-analysis of 20 studies shows that serum and red blood cell (RBC) folate levels are higher in patients with gestational diabetes than without gestational diabetes. Subgroup analysis suggests that patients with gestational diabetes have higher serum and RBC folate levels in the second trimester than in those without gestational diabetes, while RBC folate levels in patients with gestational diabetes were higher in the first trimester than those without gestational diabetes. Overall, higher serum folate levels are associated with a slight increase in the odds of gestational diabetes when compared with lower serum folate levels (112107).
• Diabetic neuropathy. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with diabetic neuropathy shows that taking a combination of B vitamins, including folic acid (L-methylfolate), vitamin B12 (methylcobalamin), and vitamin B6 (pyridoxal-5'-phosphate), for 24 weeks does not improve neural dysfunction based on vibration perception, but does seem to improve total neuropathy symptoms, when compared with placebo. These symptoms, which include both sensation and pain, decreased by 25% with the B vitamin combination, compared with only 15% in those taking placebo (90375).
• Epilepsy. It is unclear if oral folic acid reduces seizure frequency. Details: A meta-analysis of preliminary clinical research shows that taking folic acid does not reduce seizure frequency in patients with epilepsy (50124). However, there is some speculation that folate deficiency might be linked to increased seizure frequency. A preliminary clinical study in folate-deficient children with epilepsy shows that taking folic acid 5 mg daily for 3 months reduces seizure frequency when compared to baseline, but not when compared with a control group that is not deficient in folate (99371).
• Erectile dysfunction (ED). Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in males with mild erectile dysfunction, overweight or obesity, and normal to low androgen levels shows that taking a combination product containing folic acid 400 mcg, alpha-lipoic acid, myo-inositol, and apple (Sinopol Forte, Laborest) improves measures of erectile dysfunction when compared to baseline (111674). The validity of these effects is limited by the small sample size and the lack of a comparator group, and it is unclear if these effects are due to folic acid, other ingredients, or the combination.
• Esophageal cancer. Higher dietary folate intake is associated with a lower risk of esophageal cancer. Details: One meta-analysis of observational research has found that higher levels of dietary folate are associated with a 34% lower risk of esophageal squamous cell carcinoma and a 50% lower risk of esophageal adenocarcinoma when compared with low levels of dietary folate (50208). Another meta-analysis of observational research has found that consuming high amounts of folate is associated with a 36% decrease in the odds of esophageal cancer when compared with lower dietary folate intake (100950).
• Fenofibrate (Tricor)-induced hyperhomocysteinemia. Folic acid seems to attenuate increases in homocysteine in people taking fenofibrate. Details: A small open-label clinical trial in patients taking fenofibrate shows that adding folic acid 10 mg every other day might reduce elevated plasma homocysteine levels by up to 59% when compared with taking fenofibrate alone (9321).
• Gastric cancer. It is unclear if oral folic acid reduces gastric cancer risk. Details: Observational research has found that taking folic acid reduces the risk of gastric cardia adenocarcinoma by 17% and the risk of noncardia gastric cancer by 33%, but does not reduce the risk of gastric cancer overall (50208). Also, a meta-analysis of 13 small clinical studies in patients with gastric precancerous conditions shows that taking folic acid 20-30 mg daily for 3-6 months improves gastric mucosal atrophy and intestinal metaplasia but does not seem to improve symptoms when compared with a control (110448). Whether these findings are associated with a lower risk of gastric cancer is unclear.
• Gout. It is unclear if oral folic acid reduces the risk for gout. Details: An observational study has found that increased dietary folate intake is associated with a lower incidence of gout (50454).
• Head and neck cancer. It is unclear if oral folic acid is beneficial for head and neck cancer prevention. Details: Population research has found that the highest intake of dietary folate is associated with a 50% reduced risk of head and neck cancer when compared with the lowest intake of folate. Each 100 mcg increase per day seems to reduce the risk by about 4% (96151).
• Hearing loss. It is unclear if oral folic acid prevents hearing loss. Details: Low levels of serum folate seem to be a risk factor for sudden sensorineural hearing loss in adults (21283). Observational research in females has found that serum folate levels in the lowest quintile are associated with a 19% increased risk for hearing loss when compared with levels in the second quintile. Also, folate levels in the highest quintile are associated with a 12% lower risk of hearing loss when compared with the second quintile (109807). A clinical study in older adults from the Netherlands shows that taking folic acid 800 mcg daily for 3 years slows the decline of age-related low-threshold hearing loss when compared with placebo (15163). However, at the time of this study, folate enrichment of foods was not allowed in the Netherlands. As a result, baseline folate levels in this study population were about 50% lower than in the US population. The effect of folic acid supplementation in people with higher baseline folate levels is unclear.
• Infertility. It is unclear if oral 5-methyltetrahydrofolate (5-MTHF) in combination with vitamin B6 and vitamin B12 is more beneficial than folic acid alone for increasing pregnancy rate in females undergoing assisted reproductive technology (ART). Details: Retrospective research from Italy suggests that taking 5-MTHF 400 mcg, vitamin B12 5 mcg, and vitamin B6 3 mg daily results in clinical pregnancy and live birth rates of approximately 60% and 49%, respectively, compared with 45% and 35% of those taking folic acid 400 mcg daily. A sub-analysis suggests that beneficial effects on pregnancy rates are limited to individuals aged less than 40 years (109189). The findings from this study are limited by its retrospective design. Also, it is unclear if these findings are generalizable to countries with folate fortification.
• Kidney failure. It is unclear if oral folic acid is beneficial in patients with kidney failure. Details: Because hemodialysis removes folate from the body, there is concern that folate deficiency may cause complications in patients with kidney failure receiving hemodialysis. Observational research in Taiwanese patients with kidney failure undergoing hemodialysis has found that taking folic acid 5 mg daily for an average of 5.8 years is associated with a 31% lower risk of arteriovenous access thrombosis when compared with folic acid 5 mg weekly. However, daily folic acid supplementation was not linked to a lower risk of cardiovascular events, cancer, or mortality when compared with weekly folic acid (110120). Oral folic acid has also been evaluated in combination with other ingredients. A small, low-quality clinical study in adults with kidney failure undergoing regular hemodialysis shows that taking oral folic acid 30 mg daily with thiamine 90 mg daily for 96 weeks reduces overall mortality by 67% and improves cognitive scores by 31% when compared with no intervention (107724). It is unclear if these findings are due to folic acid, thiamine, or the combination.
• Lometrexol toxicity. While oral folic acid might reduce lometrexol toxicity, intravenous folic acid does not seem to help. Details: In a phase I trial, intravenous folic acid 5-25 mg administered 1 hour or 3 hours prior to lometrexol 15-30 mg/m2 every 3 weeks does not seem to reduce cumulative lometrexol toxicity (2161). However, in a phase II study, taking oral folic acid 3 mg/m2 daily in addition to lometrexol 10 mg/m2 weekly seems to attenuate cumulative toxicity and improve its tolerability in cancer patients (104948).
• Low birth weight. It is unclear if oral folic acid supplementation during pregnancy reduces the risk of a low birth weight. Details: Clinical research shows that supplementation with folic acid 200 mcg to 5 mg daily during pregnancy increases mean birth weight when compared with placebo (91307). Furthermore, some population research has found that pre- or peri-conception folic acid supplementation, usually 400 mcg daily, is associated with a reduced risk of a child born small-for-gestational age. However post-conception folic acid supplementation is not associated with reduced risk (91304,103983). An observational study in pregnant Chinese patients found that supplementation with folic acid is associated with a 20% lower odds of low birth weight when compared with no supplementation. This association was observed when folic acid was used both before conception and during pregnancy for at least 24 weeks or during pregnancy only for at least 12 weeks. Increased dietary folate intake was not linked to a lower risk of low-birth-weight infants (110446). However, other observational research has found no association between folic acid supplementation during pregnancy and the risk for small-for-gestational age births (110447).
• Lung cancer. It is unclear if oral folic acid reduces lung cancer risk. Details: There does not appear to be a relationship between deficiency of folate and lung cancer (9454). However, consuming at least 130.4 mcg of folate per 1000 kcal daily seems to reduce the risk of lung cancer by 40% in former smokers when compared to those with lower dietary folate intake (50065).
• Melanoma. It is unclear if oral folic acid reduces melanoma risk. Details: Population research has found that folic acid supplementation of 2-2.5 mg daily in combination with vitamin B6 and vitamin B12 is linked with a 53% reduced risk of melanoma (91312).
• Metabolic syndrome. Although there is interest in using oral folic acid for metabolic syndrome, there is insufficient reliable information about the clinical effects of folic acid for this condition.
• Nitrate tolerance. It is unclear if oral folic acid helps to prevent the development of tolerance to treatment with nitroglycerin. Details: Some clinical evidence suggests that taking folic acid 1 mg daily for 1 week does not prevent the development of nitroglycerin-induced endothelial dysfunction or tolerance in healthy individuals (50442). However, other research suggests that taking folic acid 10 mg daily for 1 week prevents nitric oxide synthase dysfunction caused by continuous nitroglycerin (9316).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral folic acid is beneficial for NAFLD. Details: A cross-sectional analysis suggests that adults with NAFLD have lower levels of serum folate and its major component 5-MTHF when compared with healthy controls. Additionally, adults with NAFLD seem to consume less supplementary and dietary folate when compared with healthy controls. Overall, serum folate levels are negatively associated with the risk of NAFLD, and inadequate folate intake is associated with an increased risk of NAFLD (112104).
• Oral clefts. It is unclear if oral folic acid reduces the risk of oral clefts in infants. Details: Observational research has found that maternal folic acid supplementation is associated with an up to 49% reduced risk of cleft lip with or without cleft palate (50220,104921). Furthermore, a large clinical trial in pregnancies at-risk for oral cleft suggests that taking a higher dose of folic acid 4 mg from pre-conception until the end of the first trimester results in a similar oral cleft recurrence rate of 2.5%, compared with a 2.9% recurrence with a lower dose of folic acid (400 mcg). Both doses demonstrate a lower incidence of oral clefts when compared with historical rates of 6.3% (91322). Although there is speculation that genetic markers of folate status impact the effect of folic acid on orofacial cleft incidence, the current data do not show a relationship (104921).
• Overall mortality. It is unclear if oral folic acid reduces the risk of overall mortality. Details: Observational research in US adults has found that dietary intake of folic acid in the highest quintile is associated with a 14% to 23% lower risk of all-cause mortality and a 41% to 47% lower risk of cardiovascular mortality when compared with the lowest quintile of dietary folic acid intake (110451).
• Pancreatic cancer. It is unclear if oral folic acid reduces pancreatic cancer risk. Details: Consuming greater than 280 mcg daily of dietary folate is associated with a decreased risk of exocrine pancreatic cancer (9327). A meta-analysis of case-control and cohort studies suggests that consuming higher amounts of dietary folate reduces the risk of pancreatic cancer by 51% compared to low levels of dietary folate (50208). However, another meta-analysis of prospective cohort studies suggests that folate/folic acid intake does not significantly affect the overall risk of pancreatic cancer (50499). The contradictory results may be associated with the form of intake or may be related to the gender of the participants. A meta-analysis of clinical research shows that dietary folate, but not folic acid, significantly reduces the risk of pancreatic cancer (50387). Also, one meta-analysis of observational studies has found that high dietary folate decreases the risk of pancreatic cancer in females, but not males (50387).
• Peripheral neuropathy. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows taking a combination of folic acid 400 mcg, vitamin B12 3 mcg, and uridine monophosphate 50 mg daily (Keltican) for 60 days reduces pain associated with peripheral neuropathy. Use of this product reduces pain intensity by approximately 44%, with loss of burning pain in approximately 50% of patients, strong tingling or pricking in approximately 57% of patients, strong pain attacks in 92% of patients, and numbness in 90% of patients when compared with baseline. Radiating pain and the use of concomitant medications are also reduced (90384). The validity of this finding is limited by the lack of a comparator group. Furthermore, it is unclear if the benefits are due to folic acid, other ingredients, or the combination.
• Pharyngeal cancer. It is unclear if oral folic acid reduces pharyngeal cancer risk. Details: Population research has found that intake of folic acid and folate from natural, fortified, and supplemented sources, may protect against oropharyngeal cancer. Intake of at least 258-816 mcg total folate/folic acid reduces the odds by 35% when compared with intakes of less than 344 mcg. Furthermore, folate/folic acid may be more beneficial for oral cancer versus pharyngeal cancer and in heavy alcohol users versus non users or light users (91302).
• Polycystic ovary syndrome (PCOS). It is unclear if oral folic acid is beneficial for PCOS. Details: One clinical study in overweight or obese patients with PCOS shows that taking folate 1 mg or 5 mg daily for 8 weeks modestly reduces levels of homocysteine, as well as insulin resistance, when compared with placebo. However, only the 5 mg dose modestly reduces insulin, total cholesterol, and low-density lipoprotein (LDL) cholesterol levels. Neither dose appears to affect fasting plasma glucose, high-density lipoprotein (HDL) cholesterol, or triglyceride levels when compared with placebo (109200). Other clinical research in patients with PCOS taking metformin shows that taking folate 400 mcg daily for 6 months does not affect glycemic parameters, plasma lipid levels, or hormone levels when compared with placebo (109194). The reasons for discrepancies between studies are unclear but may relate to patient characteristics. One study included only overweight or obese individuals with at least two of the three PCOS criteria, whereas the other study limited enrollment to patients in any weight category but with all three PCOS criteria (109194,109200).
• Pregnancy-induced hypertension. It is unclear if oral folic acid reduces the risk of hypertension during pregnancy. Details: Population research has found that taking folic acid during pregnancy is not associated with a reduced risk of gestational hypertension (91308,99370,99372).
• Restless legs syndrome (RLS). Although there is interest in using oral folic acid for RLS, there is insufficient reliable information about the clinical effects of folic acid for this condition.
• Schizophrenia. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination of folic acid 2 mg and vitamin B12 400 mcg daily for 16 weeks improves negative symptoms when compared with placebo in patients with schizophrenia who have persistent symptoms and a specific genetic variant of the folate transporter gene FOLHI. This variant normally results in reduced folate absorption. However, in patients without this genetic variant, folate is not beneficial with respect to negative symptom improvement (90387).
• Sickle cell disease. Oral folic acid has only been evaluated in combination with other B vitamins; its effect when used alone is unclear. Details: Preliminary clinical research in adults with sickle cell disease shows that taking vitamin B12 4.2-6 mcg, folic acid 700 mcg, and vitamin B6 4.2-6 mg daily might lower homocysteine levels. However, it is unknown if this will reduce the risk of endothelial damage in these patients (9324).
• Suicidal ideation. It is unclear if oral folic acid reduces the risk of suicidal ideation or suicide attempts. Details: One observational study has evaluated the association between folic acid supplementation and suicidal events in patients with various underlying conditions, including 12% with depression, 15% with anxiety, and 46% with pain. This within-person cohort study found that filling a prescription for folic acid 0.4-5 mg daily, either alone or as part of a multivitamin, is associated with a 44% reduced rate of suicidal events during the months after the prescription when compared with the months without the prescription. For the 48% of patients who received folic acid 1 mg daily, each additional month of taking the prescription was associated with a 5% decrease in suicidal events (109201). Prospective clinical research is needed to confirm any benefits of folic acid and to determine whether baseline folate deficiency plays a role in these outcomes. More evidence is needed to rate folic acid for these uses.

(Read more about FOLIC ACID)

POSSIBLY INEFFECTIVE

• Diarrhea. Oral gelatin tannate does not seem to be beneficial for diarrhea treatment in infants and young children. Details: A pooled analysis of three clinical trials shows that taking gelatin tannate 250-500 mg four times daily for 5 days does not reduce the duration of diarrhea or stool frequency in infants and young children with acute diarrhea and gastroenteritis when compared with placebo (103296).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Although there has been interest in using oral gelatin for aging skin, there is insufficient reliable information about the clinical effects of gelatin for this purpose.
• Beta-thalassemia. It is unclear if oral gelatin is beneficial for beta-thalassemia. Details: Preliminary clinical research in pregnant adults with minor or intermediate beta-thalassemia and mild iron-deficiency anemia shows that taking a specific form of gelatin made from donkey hide, colla corii asini, 15 grams daily for 4 weeks, increases hemoglobin by 11%, compared with a 5% reduction in those receiving no treatment (97634).
• Brittle nails. Although there has been interest in using oral gelatin for brittle nails, there is insufficient reliable information about the clinical effects of gelatin for this purpose.
• Exercise-induced muscle soreness. Although there has been interest in using oral gelatin for exercise-induced muscle soreness and damage, there is insufficient reliable information about the clinical effects of gelatin for this purpose.
• Joint pain. Although there has been interest in using oral gelatin for general joint pain, there is insufficient reliable information about the clinical effects of gelatin for this purpose.
• Obesity. Although there has been interest in using oral gelatin for weight loss, there is insufficient reliable information about the clinical effects of gelatin for this purpose.
• Osteoarthritis. Although there has been interest in using oral gelatin for osteoarthritis, there is insufficient reliable information about the clinical effects of gelatin for this purpose.
• Osteoporosis. Although there has been interest in using oral gelatin for osteoporosis, there is insufficient reliable information about the clinical effects of gelatin for this purpose.
• Rheumatoid arthritis (RA). Although there has been interest in using oral gelatin for RA, there is insufficient reliable information about the clinical effects of gelatin for this purpose.
• Ulcerative colitis. Rectal gelatin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults admitted to the hospital in China with mild to moderate ulcerative colitis lesions shows that administering a 1-gram suppository containing a specific form of gelatin made from donkey hide, colla corii asini, and multiple other ingredients rectally for 3 months improves diarrhea and bloody stool symptom scores when compared with an 0.8-gram suppository containing the same ingredients. Recurrence at 12 months occurred in approximately 10% of the patients who received the higher-dose combination product compared with 47% of patients who received the lower dose. Patients in each group received 2 suppositories twice daily for the first month, 1 suppository twice daily for the second month, and 1 suppository once daily for the third month (109673). The interpretation of these results is limited by the lack of comparison to placebo or active control with known effectiveness for ulcerative colitis.
• Uterine fibroids. Oral gelatin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Meta-analyses of a small number of preliminary clinical trials show that taking traditional Chinese medicines containing multiple ingredients including ejiao, a gelatin made from donkey hide, modestly reduces the volume of uterine fibroids and fibroid-related symptoms more effectively than mifepristone. When used in combination with mifepristone, benefits exceed those of mifepristone alone (106850). It is unclear whether any benefits are related to gelatin, one or more of the other ingredients, or their combination.
• Wrinkled skin. Although there has been interest in using oral gelatin for wrinkled skin, there is insufficient reliable information about the clinical effects of gelatin for this purpose. More evidence is needed to rate gelatin for these uses.

(Read more about GELATIN)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Androgenic alopecia. Although there is interest in using oral horsetail for alopecia, there is insufficient reliable information about the clinical effects of horsetail for this condition.
• Hypertension. Oral horsetail seems to reduce blood pressure in patients with hypertension. Details: A clinical trial in patients with stage 1 systemic arterial hypertension shows that taking horsetail extract 900 mg daily for 3 months decreases systolic and diastolic blood pressure by 13 mmHg and 8 mmHg, respectively, and is similarly effective to hydrochlorothiazide 25 mg daily (108849). The validity of this finding is limited due to high withdrawal rates and low adherence to treatment protocols.
• Kidney stones (nephrolithiasis). Although there is interest in using oral horsetail for kidney stones, there is insufficient reliable information about the clinical effects of horsetail for this condition.
• Obesity. Although there is interest in using oral horsetail for weight loss, there is insufficient reliable information about the clinical effects of horsetail for this purpose.
• Osteoporosis. It is unclear if oral horsetail is beneficial for osteoporosis. Details: Preliminary clinical research shows that taking two tablets of either dried horsetail extract or a specific combination of horsetail extract with calcium (Osteosil Calcium) daily for 2-month intervals separated by 2 weeks of no treatment for up to one year can increase bone density when compared with no treatment in postmenopausal patients with osteoporosis. The effect of horsetail extract plus calcium (Osteosil Calcium) seems to be greater than the effect of dried horsetail extract alone (55578).
• Tonsillitis. Oral horsetail has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children with acute non-bacterial tonsillitis shows that taking a specific combination product (Imupret) for 10 days in addition to standard symptomatic therapy accelerates recovery by a small amount when compared with symptomatic therapy alone. Overall treatment response after 10 days occurred in 82% of patients taking the combination product compared with 65% of patients receiving symptomatic therapy alone. Withdrawal from antipyretic drugs occurred approximately one day earlier in children using the horsetail product. Per 100 grams, Imupret provides 29 grams of an alcoholic extract produced from horsetail 0.5 grams, marshmallow root 0.4 grams, chamomile flowers 0.3 grams, walnut leaves 0.4 grams, English walnut leaves 0.4 grams, yarrow 0.4 grams, oak bark 0.2 grams, and dandelion 0.4 grams. In children aged 6-11 years, 15 drops 6 times daily for 5 days and then 15 drops 3 times daily for 5 days was used. In children aged 12-18 years, 25 drops 6 times daily for 10 days was used. (100347). Due to the small difference between the two groups and the open-label design, the clinical relevance of this study is unclear. Also, it is unclear if these benefits are due to horsetail, the other ingredients, or the combination.
• Urinary incontinence. Oral horsetail has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific supplement (Urox, Seipel Group) 840 mg, containing a combination of horsetail stem, three-leaf caper, and lindera root daily with food for 8 weeks modestly decreases urinary frequency, stress incontinence, and urgency incontinence when compared with placebo in patients with urinary incontinence and/or overactive bladder (97575). It is unclear if these effects are due to horsetail, the other ingredients, or the combination.
• Urinary tract infections (UTIs). Although there is interest in using oral horsetail for UTIs, there is insufficient reliable information about the clinical effects of horsetail for this condition. More evidence is needed to rate horsetail for these uses.

(Read more about HORSETAIL)

POSSIBLY EFFECTIVE

• Metabolic syndrome. Oral inositol seems to modestly improve lipid parameters, blood pressure, and insulin resistance in patients with metabolic syndrome. Details: Some clinical research in postmenopausal adults with metabolic syndrome following a low-calorie diet shows that taking myo-inositol 2 grams twice daily for one year reduces total cholesterol by 29 mg/dL, triglycerides by 64 mg/dL, systolic and diastolic blood pressure by 9 mmHg and 6 mmHg, respectively, increases high-density lipoprotein (HDL) cholesterol by 6 mg/dL, and improves insulin resistance when compared with placebo. It did not reduce body mass index or waist circumference in these patients (91554). A meta-analysis of clinical studies in a mixed population shows similar effects on blood pressure, especially among postmenopausal adults with metabolic syndrome, at durations exceeding 8 weeks, and at doses of at least 4 grams (108820). Inositol has also been evaluated in combination with other ingredients to treat metabolic syndrome. A clinical study in postmenopausal adults with metabolic syndrome and at risk for breast cancer shows that taking a combination of inositol and alpha-lipoic acid daily for 6 months, in combination with a low-calorie diet, reduces insulin resistance (HOMA-IR) by at least 20% when compared with a low-calorie diet alone. Also, taking inositol and alpha-lipoic acid seems to increase HDL cholesterol by about 6% and reduce triglycerides by 5% when compared to baseline (91543). Another small clinical study in adults with metabolic syndrome shows that taking a specific combination product containing D-chiro-inositol 40 mg, Ceylon cinnamon 250 mg, glucomannan 1000 mg, and inulin 200 mg orally daily for 4 months modestly improves total cholesterol levels and body weight, but not serum glycated hemoglobin, low-density lipoprotein levels, high-density lipoprotein levels, or triglyceride levels when compared with no intervention (114552).
• Polycystic ovary syndrome (PCOS). Oral inositol, often in combination with folic acid, seems to improve some glycemic, lipid, metabolic, hormonal, and reproductive parameters in patients with PCOS. However, research is conflicting. Details: Oral inositol, most frequently in the forms of myo-inositol or D-chiro-inositol, has been evaluated for efficacy in a wide range of outcomes associated with PCOS including reproductive and pregnancy outcomes, metabolic parameters, and anthropomorphic measures. Often, inositol is taken in combination with folic acid or metformin. Inositol has been investigated for its effect on metabolic parameters that are often altered in PCOS. A meta-analysis of 9 studies in patients with PCOS shows that taking myo-inositol or D-chiro-inositol with or without folic acid marginally decreases body mass index (BMI) by about 0.5 kg/m2 when compared with placebo (111670). Inositol has also been evaluated for its effect on glucose metabolism in adults with PCOS. Meta-analyses of about 10 studies show that taking myo-inositol or D-chiro-inositol with or without folic acid reduces fasting plasma glucose by 1-4 mg/dL (98944,111670). However, evidence is conflicting on the effect of inositol on insulin levels and measures of insulin resistance (98944,111670). Additionally, most studies show that inositol does not improve measures of glucose metabolism more than metformin. The effect of inositol on lipid profiles has also been studied. A meta-analysis of 2 clinical studies and other small clinical studies show that taking inositol as D-chiro-inositol with or without folic acid modestly reduces total cholesterol and triglycerides when compared with control (2028,98944,91552). Some studies have also investigated the effect of inositol on hormone levels. Meta-analyses show that inositol modulates androgen levels as shown by reduced total and free testosterone, androstenedione, and increased sex-hormone binding globulin when compared with placebo. (2028,91552,98944,111670). The validity of these effects is limited by high heterogeneity in terms of inclusion and exclusion criteria, dose, and treatment duration within the included studies. Myo-inositol has also been compared with metformin in some clinical research, with some evidence of benefit (95085,95086). Meta-analyses of small clinical studies show that taking myo-inositol 2-4 grams daily, with or without folic acid, for 12-24 weeks does not improve fasting blood glucose, fasting insulin, insulin resistance (HOMA-IR), BMI, waist-hip circumference, or androgen levels when compared with metformin 1.5-2.5 grams daily (100705,108823,111670,111670). However, inositol seems to have a lower risk of adverse effects than metformin. These analyses are limited due to the small size, methodological issues, and high heterogeneity of the included studies. In combination with metformin, small clinical studies show that taking metformin, myo-inositol 550 mg, and D-chiro-inositol 150 mg twice daily is associated with improved lipid parameters and postprandial insulin levels when compared with metformin alone (108822). Meta-analyses and clinical studies have investigated the effect of inositol on ovulation, reproduction, and pregnancy outcomes. Some research suggests that inositol increases ovulation rate, promotes cycle normalization, and improves ovarian function in patients with PCOS (2028,91552,98944,111670). A small clinical study shows that taking myo-inositol 4 grams and folic acid 400 mcg (Inofolic, Lo.Li.Pharma) daily for three spontaneous cycles induces ovulation in about 62% of individuals with anovulatory PCOS and insulin resistance. Adding clomiphene citrate with myo-inositol induces ovulation in about 72% of the patients who remain anovulatory after treatment with myo-inositol alone (91547). Another clinical study shows that taking a combination of inositol 2 grams, folic acid 200 mcg, and N-acetyl cysteine 600 mg (Ovaric HP, Just Pharma) twice daily for 12 months improves ovulation rates in PCOS patients with oligomenorrhea, regardless of insulin sensitivity at baseline (91553). Despite evidence that inositol improves ovulation rates, it does not appear to impact pregnancy rates (111670). Some research has also investigated the effects of taking both isomers of inositol concomitantly. Taking myo-inositol 550 mg plus D-chiro-inositol 13.8 mg (Inofolic Combi, Lo.Li.Pharma) twice daily, beginning 12 weeks before ovarian hyperstimulation and continuing throughout pregnancy, improves oocyte quality when compared to treatment with D-chiro-inositol alone. The combination appears to increase fertilization rate in patients aged 35 years or younger, but not those older than 35 years (91544). Other clinical research shows that taking myo-inositol 550 mg and D-chiro-inositol 150 mg twice daily for 12 weeks improves pregnancy rates and live birth rates by an additional 10% and 11%, respectively, when compared with myo-inositol 550 mg plus D-chiro-inositol 13.8 mg. The higher-dose combination also resulted in a 15% lower rate of ovarian hyperstimulation syndrome when compared with those taking the lower dose of D-chiro-inositol (102317). Lastly, other research shows that taking myo-inositol and D-chiro-inositol together may improve metabolic parameters faster than taking myo-inositol alone (91550). Research has also evaluated the effects of inositol on other pertinent clinical outcomes in PCOS. Several small clinical studies show that taking the combination of myo-inositol and D-chiro-inositol, alone or in combination with metformin, improves menstrual cycle irregularity when compared with metformin alone, but not as much as a taking a combined hormonal contraceptive (108822,108824). The validity of these findings is limited by the unblinded nature of the studies. Also, a small clinical study shows that taking metformin with myo-inositol 550 mg and D-chiro-inositol 150 mg twice daily is associated with improved acne, but not hirsutism, at 6 months, when compared with metformin alone (108822). The validity of these findings is limited by the unblinded nature of the study. More research is needed to clarify the effect of inositol on anthropometric, metabolic, and endocrine outcomes in patients with PCOS.
• Preterm labor. Oral inositol in combination with folic acid seems to prevent preterm labor in individuals at risk for gestational diabetes. Details: A meta-analysis of five clinical trials in individuals at risk for gestational diabetes shows that taking myo-inositol plus folic acid daily, beginning during the first trimester and continuing throughout pregnancy, decreases the risk of preterm delivery by 64% when compared with folic acid alone. Patients in all but one study included in this analysis took myo-inositol 2 grams plus folic acid 200 mcg twice daily, while patients in the other study took myo-inositol 1100 mg plus D-chiro-inositol 27.6 mg and folic acid 400 mcg daily (100706). It's unclear if these results are generalizable to individuals with a low risk for gestational diabetes.

POSSIBLY INEFFECTIVE

• Acute respiratory distress syndrome (ARDS). Oral or intravenous inositol does not seem to prevent ARDS in preterm infants and may be associated with worsened outcomes. Details: Historically, small clinical trials in infants with or at risk for ARDS have suggested that myo-inositol, given parenterally and enterally for 5-10 days, might improve survival and reduce the risk of death and serious complications (2191,2192,91546). However, a large, high-quality clinical study in infants born at less than 28 weeks' gestation at risk for ARDS shows that myo-inositol 40 mg/kg given intravenously and then enterally every 12 hours for up to 70 days does not reduce the risk of death or retinopathy of prematurity (ROP). In fact, the rate of death or type 1 ROP increased by 7% in the myo-inositol group when compared to the control group, and a higher incidence of adverse events in the myo-inositol group, including poor perfusion, hypotension, and infections, led to early trial discontinuation (98946). Long-term follow-up until 24 months corrected age confirms that the initial increase in mortality rate in the myo-inositol group remained stable; however, there was no difference in a composite outcome of death or survival with moderate or severe neurodevelopmental impairment, as well as no difference in the risk of ROP, between the treatment and control groups (108819). The most recent meta-analysis, which incorporates this large clinical study, concludes that inositol supplementation does not reduce the risk of death in infants at risk for ARDS (102319).
• Anxiety. Oral inositol does not seem to be beneficial for patients with anxiety. Details: A meta-analysis of four clinical trials shows that taking inositol orally does not improve anxiety severity in patients with anxiety disorders, including obsessive-compulsive disorder, panic disorder, or post-traumatic stress disorder, when compared with placebo (91549).
• Depression. Oral inositol does not seem to be beneficial for patients with depression. Details: Guidelines from the World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that inositol in doses up to 12 grams daily is not currently recommended as monotherapy or adjunctive use for major depressive disorder due to a lack of evidence for efficacy (110318). Additionally, a meta-analysis of seven clinical trials shows that inositol does not significantly improve symptoms of depression in patients with bipolar depression, major depressive disorder, or premenstrual dysphoric disorder (PMDD) (91549). While limited research shows that patients receiving inositol for 4 weeks may improve, patients initially responding to inositol seem to relapse rapidly upon discontinuation of treatment (2026,2185). Additionally, taking inositol with a selective serotonin reuptake inhibitor (SSRI) doesn't appear to improve the effectiveness of SSRI therapy or improve depression in SSRI treatment failures (2025,10851).
• Diabetic neuropathy. Oral inositol does not seem to be beneficial for patients with diabetic neuropathy. Details: Most preliminary clinical research shows that taking inositol orally doesn't improve the symptoms of diabetic neuropathy (2193,2194,2195).
• Retinopathy of prematurity. Oral or intravenous inositol does not seem to prevent retinopathy of prematurity (ROP) in preterm infants. Details: A meta-analysis of six clinical trials shows that myo-inositol, given parenterally and/or enterally, does not seem to reduce the risk of ROP when compared with placebo in preterm infants (100704). A large, high-quality clinical study included in this meta-analysis shows that myo-inositol 40 mg/kg given intravenously and then enterally every 12 hours for up to 70 days does not reduce the risk of death or ROP in infants born at less than 28 weeks' gestation. In fact, the rate of death or type 1 ROP increased by 7% in the myo-inositol group when compared with placebo and a higher incidence of adverse events in the myo-inositol group, including poor perfusion, hypotension, and infections, led to early trial discontinuation (98946). Long-term follow-up until 24 months corrected age confirms that the initial increase in mortality rate in the myo-inositol group remained stable; however, there was no difference in a composite outcome of death or survival with moderate or severe neurodevelopmental impairment, as well as no difference in the risk of ROP, between the treatment and control groups (108819).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related testosterone deficiency. It is unclear if oral D-chiro-inositol is beneficial in patients with age-related testosterone deficiency. Details: A very small clinical study in males aged 65-75 years with low-normal morning testosterone levels and signs and symptoms of androgen deficiency shows that taking D-chiro-inositol 600 mg twice daily for 30 days improves sexual function and physical strength when compared with baseline (108821). The validity of these findings is limited by the lack of a comparator group.
• Bipolar disorder. It is unclear if oral inositol is beneficial in patients with bipolar disorder. Details: Evidence is conflicting on whether inositol helps treat bipolar disorder in children. One very small preliminary study in children aged 5-12 years with bipolar disorder not on concomitant mood-stabilizing medications shows that taking inositol 80 mg/kg (maximum 2 grams) daily for 12 weeks reduces manic symptoms when compared to baseline. Additionally, taking a combination of inositol 80 mg/kg and high eicosapentaenoic acid omega-3 fatty acid capsules (EPA; Nordic Naturals) 1650-3000 mg daily for 12 weeks reduces manic and depressive symptoms when compared to baseline (95092). However, another more recent study with the same intervention and protocol shows that the combination of inositol and high eicosapentaenoic acid omega-3 fatty acid reduces symptoms of depression, but does not improve manic symptoms, when compared with either ingredient taken alone (111676).
• Chemotherapy-induced leukopenia. Oral inositol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults undergoing breast cancer surgery and adjuvant chemotherapy shows that taking inositol orally 390 mg twice daily and applying IP-6 gel 4% twice daily to the surgical site, starting 2 weeks before adjuvant chemotherapy and stopping 2 weeks after the last cycle, attenuates reductions in white and red blood cell counts when compared with no intervention. Using inositol and IP-6 also improves breast and arm symptom scores and some quality of life scores; however, these improvements were not consistent over time.
• Diabetes. It is unclear if oral inositol is beneficial for the treatment of type 1 diabetes or the prevention of gestational diabetes. Details: Preliminary clinical research in patients with type 1 diabetes and a body mass index of at least 25 kg/m2 shows that taking a specific combination product containing D-chiro-inositol and folic acid (Chirofol 500, LJ Pharma) daily for 6 months, along with insulin therapy, decreases glycated hemoglobin (HbA1c) by approximately 0.5% when compared to taking folic acid alone with insulin therapy. However, there was no difference between groups with respect to insulin resistance or body mass index (95088). Most research shows that taking inositol during pregnancy prevents gestational diabetes. However, most studies conducted to date are of low quality and it is unclear if the results are generalizable. Meta-analyses of 4-7 clinical studies in pregnant adults, some with overweight and obesity, shows that taking myo-inositol 200-4000 mg daily may reduce the risk of gestational diabetes and gestational hypertension, improve 1- and 2-hour glucose tolerance test results, and reduce insulin requirements. Inositol may also be associated with improved infant outcomes such as increased gestational age at birth and reduced preterm delivery but does not seem to influence birth weight, NICU admission rate, neonatal hypoglycemia, the incidence of shoulder dystocia, macrosomia or cesarian delivery when compared with control (111664,111667,111671,111677,114560). The validity of these effects is limited by significant heterogeneity within the included studies, concerns about blinding, and overall low-quality evidence. Most clinical research shows that taking myo-inositol 2 grams plus folic acid 200 mcg twice daily (usually as Inofolic, Lo.Li. Pharma International), beginning during the first trimester and continuing throughout pregnancy, decreases the incidence of gestational diabetes by 57% to 92% when compared with folic acid alone in patients at risk for gestational diabetes. Myo-inositol seems to be more effective than D-chiro-inositol (91545,91548,95083,95084,100706,103750,104688). Subgroup analysis suggests that supplementation with lower doses of inositol, mimicking natural inositol occurring in the body, may not be effective at preventing gestational diabetes (114560). However, this analysis may have been inadequately powered to detect a difference between groups, and it is further limited by heterogenous methods between trials, including duration, population, and product. Other evidence is conflicting about whether inositol prevents gestational diabetes. One clinical study shows that taking a combination of myo-inositol 1.1 grams, D-chiro-inositol 27.6 mg, and folic acid 400 mcg (Inofolic Combi, Lo.Li. Pharma International) daily during pregnancy does not decrease the incidence of gestational diabetes when compared with folic acid alone in patients with a family history of diabetes (95082,103750). In patients eventually diagnosed with gestational diabetes, one small clinical study shows that taking myo-inositol 2 grams reduces the number of patients requiring insulin by at least 50% (104688), although another small clinical study shows that adding D-chiro-inositol, myo-inositol, or both to folic acid does not affect insulin resistance when compared with placebo (98945).
• Dyslipidemia. Although there has been interest in using oral inositol for hypercholesterolemia and hypertriglyceridemia, there is insufficient reliable information about the clinical effects of inositol for these conditions.
• Erectile dysfunction (ED). Oral inositol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Another very small study in males with overweight or obesity, mild ED, and normal to low androgen levels shows that taking a combination product containing myo-inositol 4000 mg, alpha-lipoic acid, folic acid, and apple (Sinopol Forte) improves measures of erectile dysfunction when compared with baseline (111674). The validity of these effects is limited by the small sample size and the lack of a comparator group, and it is unclear if these effects are due to inositol, other ingredients, or the combination.
• Hypertension. Although there has been interest in using oral inositol for hypertension, there is insufficient reliable information about the clinical effects of inositol for this condition.
• Hypothyroidism. Inositol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of clinical and observational research in adults with hypothyroidism, subclinical hypothyroidism, and other thyroid disorders shows that taking a combination of inositol 600-1200 mg and selenium 83-166 mg orally daily for 6-12 months modestly improves thyroid stimulating hormone (TSH) levels and thyroxine levels when compared with control (114562). Clinical research in females aged 18 to 50 years with or at risk for subclinical hypothyroidism in Slovakia shows that taking myo-inositol 600 mg and selenium 83 mcg daily for 6 months reduces patient-reported hypothyroid symptoms including fatigue, menstrual cycle irregularity, and intolerance to heat or cold (110591). The interpretation of this result is limited by the lack of a control group. In addition, it is unclear if the effects in these studies are due to myo-inositol, selenium, or the combination.
• Infertility. It is unclear if oral inositol is beneficial in patients undergoing intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF). Details: Several small studies in patients undergoing ICSI show that taking a specific combination product containing myo-inositol 4 grams and folic acid 400 mcg (Inofolic, Lo.Li. Pharma International S.r.l) daily, starting 1-3 months before ICSI and continuing until ovulation, improves fertilization rate, but does not improve implantation or pregnancy rates, when compared with taking folic acid alone (103752,108825). However, another moderate-sized clinical study in adults with infertility undergoing ICSI and IVF shows that taking the same combination of myo-inositol 4000 mg and folic acid 400 mcg daily for 2 months starting on the third day of the cycle improves mean number of oocytes, meiosis II oocytes, 2 pronuclear embryos, and clinical pregnancy and live birth rates when compared with taking folic acid alone (111672). The effects of inositol on fertility have been studied in patients with specific comorbidities. A case-control study in long-term survivors of lymphoma suggests that taking myo-inositol 400 mg and D-chiro-inositol 45 mg (Ovofert Fast, CRL Pharma) three times daily for 12 months is associated with reductions in follicle stimulating hormone (FSH), luteinizing hormone (LH), dyspareunia, and dysmenorrhea and a modest increase in antral follicle count of the right ovary when compared with control (111673). The validity of these effects is limited by a lack of blinding. Inositol has also been evaluated in females with polycystic ovary syndrome (PCOS). A meta-analysis of clinical studies in adults with PCOS undergoing IVF or ICSI shows that inositol does not improve pregnancy rates when compared to no treatment. However, inositol may increase clinical pregnancy rates when compared with metformin (111675). Inositol has also been evaluated in combination with other ingredients. A large clinical study in females planning to conceive shows that taking a combination product containing myo-inositol 4 grams, vitamin D, riboflavin, vitamin B6, vitamin B12, zinc, and probiotics does not improve time-to-conception, clinical pregnancy rates, or live birth rates when compared with a standard micronutrient supplement. However, the supplement shortens time-to-conception in adults with overweight to durations equivalent to patients who are not overweight, but lengthens time to conception in adults with obesity when compared with placebo (111665). It is unclear whether these effects are due to inositol, other ingredients, or the combination.
• Insomnia. It is unclear if oral inositol is beneficial for improving sleep during pregnancy. Details: Clinical research shows that taking myo-inositol 2 grams plus folic acid 200 mcg (Inofolic, Lo.Li. Pharma International) before bed for 10 weeks, starting at 14 weeks gestation, improves overall measures of sleep quality by a small amount when compared with folic acid alone. However, this improvement was not maintained until 37-38 weeks' gestation. Also, the study was not limited to patients with poor sleep quality during pregnancy, but to any healthy pregnant individual (104687).
• Lithium-induced side effects. It is unclear if oral inositol is beneficial for reducing lithium-induced side effects. Details: A small clinical study suggests that taking inositol 6 grams daily for 10 weeks may improve psoriasis associated with lithium therapy when compared with baseline (11972). However, taking inositol orally does not seem to improve other lithium-induced adverse effects, such as tremor, thirst, and changes in thyroid and adrenal function (2027).
• Lung cancer. It is unclear if oral inositol is beneficial for slowing the rate of bronchial dysplasia. Details: Preliminary clinical research in smokers with bronchial dysplasia considered at high risk for lung cancer shows that taking myo-inositol (Tsuno Food Industries Co., Ltd.) 9 grams orally once daily for 2 weeks then twice daily for 6 months, does not increase the rate of complete or partial response when compared with placebo (95090).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral inositol is beneficial for NAFLD. Details: A small clinical study in adults with NAFLD and obesity shows that taking myo-inositol powder 4 grams daily for 8 weeks does not improve liver health markers, such as liver function test levels or liver steatosis, but does improve some components of lipid profiles, glycemic indices, and anthropometric measures when compared to baseline (111304) However, this study may have been inadequately powered to detect differences in some of the outcomes.
• Obesity. It is unclear if oral inositol is beneficial in patients with overweight or obesity. Details: A meta-analysis of 15 clinical studies in adults shows that taking inositol 600-4450 mg daily for 6-48 weeks decreases body mass index (BMI) by about 0.4 kg/m2. Subgroup analysis suggests that myo-inositol may be beneficial at a dosage less than 1000 mg for less than 12 weeks, especially in patients with polycystic ovary syndrome (PCOS) and overweight or obesity, with higher baseline BMI, and above 40 years of age (111666). However, the validity of this finding is limited by significant heterogeneity in the included studies.
• Obsessive-compulsive disorder (OCD). It is unclear if oral inositol is beneficial in patients with OCD. Details: One preliminary clinical study in adults with OCD shows that taking inositol 18 grams daily for 6 weeks improves Yale-Brown Obsessive Compulsive Scale scores when compared with placebo (2186). However, taking inositol does not seem to improve the severity or type of OCD symptoms in patients already taking a selective serotonin reuptake inhibitor (91556). Both of these studies were small, and treatment was administered for only 6 weeks.
• Panic disorder. Oral inositol seems to improve symptoms of panic disorder. Details: A very small clinical study shows that taking inositol 12 grams daily reduces the severity and rate of panic attacks and the severity of agoraphobia over 4 weeks of treatment when compared with placebo (2184). Another very small clinical study shows that taking inositol 18 grams daily for one month may be as effective as fluvoxamine 150 mg daily for treatment of panic disorder (10387). However, the one-month duration may not have provided adequate time to see the full effects of fluvoxamine.
• Post-traumatic stress disorder (PTSD). It is unclear if oral inositol is beneficial in patients with PTSD. Details: Preliminary clinical research shows that taking inositol 12 grams daily for 4 weeks does not improve distress when compared with placebo in patients with PTSD (91557).
• Pregnancy-induced hypertension. It is unclear if oral inositol is beneficial for preventing hypertension during pregnancy. Details: In patients with a body mass index (BMI) between 25-29.9 kg/m2, preliminary clinical research shows that taking myo-inositol 2 grams plus folic acid 200 mcg (Inofolic, Lo.Li. Pharma International) twice daily, beginning during the first trimester and continuing throughout pregnancy, decreases the incidence of pregnancy-induced hypertension by 66% when compared with folic acid alone (104688).
• Psoriasis. It is unclear if oral or topical inositol is beneficial for improving symptoms of psoriasis. Details: One small clinical study shows that taking inositol 6 grams daily for 10 weeks does not improve symptoms of psoriasis in a small group of patients when compared to baseline. However, taking this dose of inositol has a moderate effect on overall symptoms in patients with psoriasis related to lithium use (11972). Preliminary clinical research also shows that topical use of D-chiro-inositol is unlikely to be beneficial for reducing overall symptoms of psoriasis. Topical application of inositol 0.25% or 1% for 6 weeks improves overall symptoms when compared with baseline. However, the inositol-containing creams were no more effective than the control cream (104686). Inositol has also been evaluated in combination with other ingredients. A small prospective observational study in adults with mild plaque psoriasis suggests that applying amino-inositol and urea 40% cream (Inosit U40, Biogena) 1-2 times daily for 4 weeks is associated with reductions in the severity and extent of psoriasis symptoms and improvements in quality of life measures when compared to baseline (111668). The validity of these effects is limited by a small sample size, a lack of a comparator group, insufficient blinding, and the observational study design.
• Trichotillomania. It is unclear if oral inositol is beneficial for reducing hair pulling. Details: Preliminary clinical research shows that taking inositol in doses ranging from 6-18 grams daily over a period of 10 weeks is no more effective than placebo in reducing subjective or clinician-documented symptoms of hair pulling in patients with trichotillomania (95089). More evidence is needed to rate inositol for these uses.

(Read more about INOSITOL)

LIKELY EFFECTIVE

• Iodine deficiency. Oral iodine supplements, including iodized salt, are effective for improving iodine status and reducing goiter size in adults and children. Iodine supplementation is also recommended during pregnancy in areas at risk for iodine deficiency. Details: Iodine deficiency is associated with several adverse outcomes. The earliest clinical symptom of iodine deficiency is low circulating thyroid hormone and thyroid stimulating hormone (TSH), followed by thyroid goiter (7135,16747,91398). Iodine deficiency and subsequent hypothyroidism can lead to anovulation, infertility, autoimmune thyroiditis, and gestational hypertension. Iodine deficiency is also associated with increased risk of thyroid cancer (16747). Clinical research shows that taking iodine supplements, including iodized salt, improves iodine status and reduces goiter size in adults with iodine deficiency (16747,55919,103071). Studies also show that taking iodine supplementation, including iodized salt, in areas of endemic iodine deficiency, reduces goiter size in children (16747,55919). When taken during pregnancy for iodine deficiency, iodine supplements and iodized salt reduce both maternal and newborn thyroid size and thyroglobulin; however, the effect on maternal TSH is inconsistent (91399,103070). Although some clinical studies and one analysis show that perinatal use of iodine has no effect on the incidence of thyroid disorders during pregnancy (91399,97240,97241), one analysis shows that iodine supplementation reduces the risk of postpartum hyperthyroidism by 68% when compared with placebo (97240). Taking iodine supplementation before 12 weeks' gestation appears to be more effective than when taken later in pregnancy. Perinatal iodine supplementation has no effect on preterm birth rate (97240,97241). Evidence is limited to females with mild-moderate iodine deficiency; the routine use of iodine supplementation during pregnancy has not been extensively studied. For example, the effect of perinatal supplementation on newborn neurocognitive development is conflicting and the evidence is generally low quality (55976,97241,105880,108706). Despite the limited evidence, iodine supplementation is recommended in areas at risk of deficiency.
• Radiation exposure. Oral potassium iodide prevents thyroid uptake of radioactive iodine. However, it does not protect against other sources of radiation. Details: Taking potassium iodide is effective for preventing the uptake of radioactive iodine by the thyroid (7517,7518). Doses of potassium iodide protect for about 24 hours. Therefore, it should be taken daily until the risk of radiation exposure no longer exists (17575,17576).

POSSIBLY EFFECTIVE

• Conjunctivitis. Ophthalmic povidone-iodine solution seems to reduce the risk of conjunctivitis in infants. It may also improve the resolution of acute conjunctivitis in adults. It is unclear if it is beneficial in patients with adenoviral conjunctivitis. Details: A meta-analysis of low-quality clinical trials shows that povidone-iodine solutions are more effective than silver nitrate for preventing neonatal conjunctivitis. However, povidone-iodine solutions are not more effective than erythromycin or chloramphenicol (56084). Povidone-iodine in combination with dexamethasone also seems to be helpful in adults. A clinical trial in patients with acute viral conjunctivitis shows that applying povidone-iodine 0.6% with dexamethasone 0.1% four times daily for 4 days improves clinical symptoms and eradiation of viral counts when compared with placebo control (103075). A small clinical study in adults with adenoviral conjunctivitis shows that administering 4-5 drops of a povidone-iodine 5% eye drop solution within 4 days of symptom onset decreases viral load, mucoid discharge, and bulbar edema and redness on day 4 of a 21-day follow-up period, but at no other time points, when compared with a single dose of artificial tears (108705). Due to the single-dose nature of this study, the effects of continued administration are unclear.
• Diabetic foot ulcers. Topical iodine seems to help with the management of diabetic foot ulcer wounds. Details: A small clinical study in patients with diabetic foot ulcers shows that topically applying cadexomer iodine ointment (Iodosorb) for 12 weeks seems to improve healing to a similar degree as using standard treatment with gentamicin solution, streptokinase, and/or dry saline gauze (2200).
• Endometritis. Topical application of iodine prior to cesarean delivery seems to reduce the risk of endometritis. Details: A meta-analysis of eight clinical trials shows that vaginally applying povidone-iodine 1% to 10% solution immediately before cesarean delivery reduces the risk of post-cesarean endometritis by 62% when compared with saline or no cleaning. It also reduces postoperative fever by 13% and wound infection by 23% (99794). These findings are consistent with other meta-analyses (56080,103076). There seems to be no difference in benefit whether povidone-iodine 1%, 5%, or 10% is used. A network meta-analysis of clinical studies in patients having cesarean delivery suggests that povidone-iodine is no better at preventing endometritis than using chlorhexidine or metronidazole; however, there may not have been sufficient power to detect a difference (103076).
• Fibrocystic breast disease. Oral iodine seems to reduce breast pain in patients with fibrocystic breast disease. Details: Preliminary clinical research in patients with fibrocystic breast disease shows that taking sodium iodide, protein bound iodide, or molecular iodine for 6 months or longer improves mastalgia and reduces breast nodules when compared with baseline or control. Molecular iodine in doses of 70-90 mcg/kg appears to be more effective and better tolerated than the other forms (2197). Another clinical study in patients with cyclic mastalgia due to fibrocystic breast disease shows that taking tablets containing molecular iodine 3000-6000 mcg daily for 5 months reduces pain, tenderness, and nodularity in patients with cyclic mastalgia when compared with placebo. However, a lower dose of 1500 mcg daily does not appear to be beneficial (55960).
• Oral mucositis. Rinsing the mouth with a povidone-iodine solution may prevent oral mucositis from radiochemotherapy. Details: Small clinical studies in patients receiving radiation and chemotherapy for cancer shows that using an oral povidone-iodine rinse seems to reduce the risk for oral mucositis when compared with using sterile water (2198,2199).
• Periodontitis. Rinsing with povidone-iodine solution in addition to scaling and root planing seems to be modestly beneficial in patients with periodontitis. Details: A meta-analysis of mostly small clinical studies in patients with chronic periodontitis suggests that rinsing with povidone-iodine 0.1% to 10% during scaling and root planing modestly reduces the periodontal pocket depth when compared with rinsing with water or saline solution (56072).
• Postoperative infection. Povidone-iodine antisepsis prevents postoperative infection when compared with inactive controls such as normal saline and water. However, it is unclear how it compares to active controls such as chlorhexidine; practice guidelines are conflicting. Details: A meta-analysis of clinical research shows that intraoperative application of povidone-iodine reduces the risk of surgical site infection by approximately 40% when compared with saline or no irrigation (56088). However, research comparing povidone-iodine with other antiseptics such as chlorhexidine is conflicting, as are official guidelines for surgical antisepsis. Many of these discrepancies seem to be related to the presence or absence of alcohol in the preparation. A meta-analysis of clinical research comparing aqueous or alcohol-based povidone-iodine shows that using alcohol-based chlorhexidine for skin antisepsis is more effective for preventing postoperative surgical site infections and may be associated with a lower overall positive culture rate. However, since evidence for both aqueous and alcohol-based solutions of povidone-iodine were included in this study, it is unclear if this may have affected outcomes (108710). The National Institute for Health and Care Excellence (NICE) Guideline recommends chlorhexidine solution as the first choice for preparing the skin for surgery, with povidone-iodine solution as a second-line option. The antiseptic solutions are recommended to be alcohol-based as long as the surgical site is not near a mucous membrane (105906). The World Health Organization (WHO) guidelines also recommend alcohol-based chlorhexidine solutions over either alcohol-based or aqueous povidone-iodine for preventing surgical site infections. However, some experts have expressed concern that these recommendations are based on faulty evidence, as some studies used povidone-iodine preparations with lower alcohol amounts than their comparator groups (105898). In fact, the guideline from the Centers for Disease Control and Prevention (CDC) does not differentiate between povidone-iodine and chlorhexidine antiseptic solutions as long as they are alcohol-based (105905).
• Thyroid storm. Oral iodine is recommended as an adjunct to standard treatment for thyroid storm. Details: The American Thyroid Association (ATA) and the American Association of Clinical Endocrinologists (AACE) recommend a multimodality approach for treating thyroid storm that includes taking five drops of a saturated solution of potassium iodine every 6 hours (15,92699).
• Thyroid nodules. Combining oral iodine with thyroxine seems to improve the resolution of thyroid nodules. Details: A clinical study in patients with benign nodular thyroid disease and possible iodine deficiency shows that taking iodized salt 200 mcg daily in addition to thyroxine 1.5 mcg/kg daily after surgery seems to reduce the size of the thyroid remnant by 40%, compared with a 10% reduction in patients given thyroxine alone (55927). Also, one large clinical trial in patients with nodular goiter shows that taking potassium iodide 150 mcg daily in combination with levothyroxine 50-100 mcg daily for 12 months reduces nodule volume by about 17%, compared with 7% in the group using levothyroxine alone (91392).
• Venous leg ulcers. Topical cadexomer iodine seems to improve the healing of venous leg ulcers; however, it is unclear if applying povidone-iodine is beneficial. Details: A meta-analysis of four small clinical studies in patients with venous leg ulcers shows that applying cadexomer iodine results in complete healing of ulcers in 33% of patients after 4-12 weeks, compared with only 15% of patients receiving standard care alone. However, use of cadexomer iodine was associated with more adverse effects than standard care. Furthermore, preliminary clinical research shows that applying cadexomer iodine is comparable to hydrocolloid dressing, paraffin gauze dressing, dextranomer, and silver-impregnated dressings for improving the rate of complete healing. A meta-analysis of preliminary clinical research show that povidone-iodine has comparable healing rates when compared with amoxicillin, hydrocolloid dressings, and moist or foam dressings (99798). These findings were consistent with an older version of this meta-analysis (56076).

POSSIBLY INEFFECTIVE

• Catheter-related infections. Topical povidone-iodine seems to be less effective than chlorhexidine for preventing infections from intravascular catheters. Furthermore, it does not seem to reduce the risk of catheter-related urinary tract infections. Details: One meta-analysis of clinical research shows that topical application of povidone-iodine reduces the risk of bloodstream infections when applied at the insertion site of hemodialysis central venous catheters (55883). However, disinfecting catheter insertion sites using povidone-iodine seems to be less effective for preventing blood stream infections in patients receiving central venous, pulmonary artery, or peripheral artery catheters when compared with chlorhexidine solutions (55883,55916). In addition, periurethral cleansing with povidone-iodine 10% prior to bladder catheterization, as well as bladder irrigation with povidone-iodine 2% prior to urinary catheter removal, does not seem to reduce the risk of urinary tract infections when compared with placebo (56058,56126).
• Prematurity. Maternal iodine supplementation does not seem to impact neurological development in premature infants. Details: A meta-analysis of two clinical trials in premature infants shows that adding iodine to enteral or parenteral feeds does not improve mental, visual, or auditory development or reduce the risk of death when compared with no iodine supplementation (99797).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Chyluria. It is unclear if topical iodine is beneficial in patients with chyluria. Details: A small clinical study in patients with chyluria suggests that using povidone-iodine 0.2% solution as a sclerosant in renal pelvic instillation sclerotherapy (RPIS) may be as effective as using silver nitrate 1% (55970).
• Corneal ulceration. It is unclear if topical iodine is beneficial in patients with corneal ulceration. Details: Preliminary clinical research shows that administering povidone-iodine 2.5% eye drops every two hours for two weeks in addition to standard antibiotic therapy does not reduce visual impairment in patients with corneal ulcers when compared with standard antibiotic therapy alone (55971).
• Coronavirus disease 2019 (COVID-19). It is unclear if rinsing with a povidone-iodine mouthwash and using a povidone-iodine nasal spray and ointment can reduce the spread of COVID-19. Details: A small clinical study in adults with PCR-confirmed COVID-19 shows that orally swishing and gargling 25 mL of povidone-iodine (PI) 1% solution, then, into each nostril, spraying 2.5 mL of PI 1% solution and applying one dab of PI 10% ointment, and repeating this 4 times daily for 5 days does not seem to alter the quantity of viral RNA over time when compared with control (105877). The validity of this finding is limited because all study participants achieved negative viral titers on the third day of the study.
• Cutaneous sporotrichosis. It is unclear if topical iodine is beneficial in patients with cutaneous sporotrichosis; research is conflicting. Details: Anecdotal reports and case series suggest that taking saturated solution of potassium iodide (SSKI) orally is effective for most patients when used alone or in combination with another antifungal, including terbinafine or itraconazole (17562,17563,17564,17565,17566,17567,17568,17569,17570,17571) (17572,17573). In one non-controlled clinical study, treatment with SSKI, starting with 3 drops (150 mg potassium iodide) daily and titrating up, resulted in symptom resolution in about 90% of patients after about 33 days of treatment (17561). However, some patients are not able to take SSKI due to intolerable side effects (17561,17572).
• Hyperthyroidism. It is unclear if oral potassium iodide is beneficial for patients with Graves' disease undergoing total thyroidectomy. Details: A retrospective study in patients with Graves' disease undergoing total thyroidectomy shows that preoperative administration of saturated solution of potassium iodide (SSKI) 5% does not reduce the rate of postoperative complications, such as transient or permanent hypoparathyroidism, transient recurrent laryngeal nerve (RLN) palsy, definitive RLN palsy, and cervical hematoma, when compared with no preoperative administration (108707).
• Infant development. It is unclear if maternal iodine supplementation impacts neurological development in infants. Details: Three-year follow-up data from a clinical study in infants and breastfeeding females shows that maternal supplementation of iodine 150 mcg daily improves child cognitive scores, but does not affect language or motor scores, when compared with placebo. Supplementation with a higher dose of 300 mcg daily yielded similar cognitive, language, and motor scores as the 150 mcg dose (108706). This finding aligns with the daily recommended dietary allowance (RDA) of 290 mcg during lactation, which is sometimes achieved by augmenting the diet with a 150-mcg iodine supplement (7135).
• Postoperative bleeding. It is unclear if topical iodine is beneficial in patients with postoperative bleeding. Details: A small clinical study suggests that irrigating extraction sockets with povidone-iodine 1% stops bleeding in a greater number of patients following tooth extraction when compared with a saline solution (56011).
• Rhinosinusitis. It is unclear if topical iodine is beneficial in patients with rhinosinusitis. Details: A small prospective cohort study in patients with recalcitrant chronic rhinosinusitis has found that using a povidone-iodine 0.08% nasal rinse every other day for 7 weeks in addition to standard therapy improves symptoms and reduces signs of infection when compared with baseline (103074). However, one small clinical study in patients with a history of sinus surgery and acute exacerbations of chronic sinusitis shows that receiving povidone-iodine nasal irrigations twice daily for 30 days is no different than irrigations with mupirocin or normal saline for improving nasal symptoms. However, mupirocin tended to reduce bacteria count to a greater extent than the povidone-iodine solution (105878). This finding is limited due to small study size and potential lack of power to detect differences between groups.
• Thyroid cancer. It is unclear if dietary iodine is associated with complications in patients with papillary thyroid cancer. Details: A retrospective study in patients in China with papillary thyroid cancer has found that dietary intake of iodine resulting in serum concentrations greater than 90 mcg/L is associated with a 75% increased risk of cervical lymph node metastases when compared with concentrations less than 45 mcg/L (108708). Actual dietary intake of iodine was not reported, limiting the validity of this finding.
• Ventilator-associated pneumonia (VAP). It is unclear if oral iodine rinse is beneficial for the prevention of VAP. Details: A small clinical study in patients with severe head trauma suggests that regularly rinsing the throat with 20 mL of povidone-iodine 10% solution decreases the risk for VAP when compared with using a saline rinse (56003).
• Wound healing. It is unclear if topical iodine is beneficial for wound healing. Details: A meta-analysis of clinical research shows that topical iodine, as cadexomer iodine or povidone-iodine, is superior to non-antiseptic dressings and some antiseptic agents, such as silver sulfadiazine, for reducing wound size. However, iodine seems to be less effective than local antibiotics such as rifamycin (56083). More evidence is needed to rate iodine for these uses.

(Read more about IODINE)

EFFECTIVE

• Anemia of chronic disease. Oral and intravenous iron in combination with erythropoiesis-stimulating agents (ESAs) are effective for treating anemia of chronic disease. Details: Iron supplementation with ESAs is effective for treating anemia associated with chronic kidney disease (CKD) or chemotherapy. During therapy with ESAs, iron levels should be monitored and supplementation provided as needed to ensure that the response is not limited by lack of iron for erythropoiesis (1087,1091,20110,20111,110192). Research shows that intravenous iron appears to be more effective than oral supplements for this purpose (20112,20113). In patients with CKD, intravenous iron at total doses from 2232 mg over 6 months to 1020 mg over one week increases hemoglobin levels more than oral doses of 4-6 mg/kg daily or 325 mg daily for up to 6 months (20112). Some research has evaluated the effect of intravenous or oral iron in patients not treated with ESAs. In patients with cancer or CKD, oral iron supplements have been shown to improve iron status (110184,110192). However, overall benefits of iron alone remain unclear in treated or untreated patients with cancer and more research is needed to rule out an increase in mortality and to determine any effect on blood transfusion requirements (110192). Preliminary clinical research shows that children aged 6 months to 10 years with HIV and anemia who take elemental iron 3 mg/kg daily along with a multivitamin for 3 months have a 41% lower chance of having persistent anemia at 3 months when compared with multivitamins alone (95432).
• Iron deficiency anemia. Oral and intravenous iron are effective for treating or preventing iron deficiency anemia. The benefits of iron supplementation in people with iron deficiency without anemia are unclear. Details: Oral iron supplements, mainly as ferrous sulfate, are effective for treating and preventing iron deficiency anemia in adults, children, and infants (1089,7135,17495,17496,17497,103806,20114,20115,91183,96621)(104680,104681,112601). Other forms are also effective, including sodium iron ethylenediaminetetra-acetate (NaFeEDTA), iron(III)-hydroxide polymaltose complex (IPC), iron protein succinylate, iron bisglycinate, and lactoferrin with iron (20117,20118,110189). Treatment with iron supplements should increase hemoglobin levels by 1 gram/dL every 2-3 weeks. However, even after hemoglobin has normalized, it may take up to 4 months for iron stores to be replenished (17497). Historically, treatment of iron deficiency anemia with oral iron supplements has typically consisted of a daily dosing regimen, often taken in divided doses to reduce adverse effects. In more recent years, however, intermittent iron supplementation (1-3 doses/week) has become preferred for some patients, particularly those with mild anemia, due to better absorption and a possible reduction in side effects compared to daily dosing. One small clinical study shows that taking ferrous sulfate 60 mg on alternate days in single doses improves iron absorption when compared to once daily dosing (96630). Another small clinical study in females with iron-deficiency anemia shows that fractional iron absorption is 40% to 50% higher with alternate-day dosing compared with daily dosing. Furthermore, total iron absorption was shown to be similar for alternate day dosing of elemental iron 200 mg compared with daily dosing of 100 mg, but the incidence of gastrointestinal adverse effects may be lower for the alternate day dosing regimen (101514). A meta-analysis of 25 clinical trials, including 10,996 menstruating females with or without pre-existing iron deficiency and/or anemia, shows that intermittent iron reduces the risk of anemia and increases hemoglobin and serum ferritin when compared with placebo or no intervention. This meta-analysis did not identify differences in the risk of anemia, hemoglobin, or serum ferritin between intermittent and daily iron supplementation. However, it did show that females receiving intermittent dosing had a 59% reduction in the risk for adverse effects. The validity of these findings is limited by significant heterogeneity in the enrolled populations and selected dosing strategies, including frequency of intermittent dosing, total weekly dose, and duration of follow-up. In addition, the subgroup analyses performed by baseline anemia, hemoglobin, and serum ferritin, as well as duration of follow-up, showed differing overall conclusions when comparing intermittent and daily iron supplementation. While intermittent dosing appears to be beneficial when compared with daily dosing for some patients with iron deficiency anemia, intermittent dosing may be less effective than daily iron supplementation in some patients (103806). For patients with severe anemia, twice daily dosing may be preferred to alternate day dosing due to faster response. A small clinical study in patients with iron deficiency anemia shows that taking ferrous sulfate 200 mg twice daily is more effective at increasing hemoglobin levels by 3 weeks when compared with ferrous sulfate 400 mg taken on alternate days in single doses (102864). Intermittent iron supplementation has also been investigated in children. A meta-analysis of clinical research in children and adolescents with or without pre-existing iron deficiency and/or anemia shows that taking iron supplements 1-2 times weekly is similarly effective as 3-7 times weekly for decreasing iron deficiency and iron deficiency anemia. However, ferritin and hemoglobin levels increased to a greater extent with 3-7 times weekly supplementation (112601). Blood transfusion may be required for some patients with severe iron deficiency anemia who have symptoms such as dyspnea and fatigue (17497). Intravenous iron should be considered in patients who cannot tolerate oral iron or in patients with chronic bleeding or intestinal malabsorption (17497). Guidelines from the British Society of Gastroenterology recommend treatment with iron while awaiting investigations to rule out gastrointestinal issues in adults in the absence of an alternative explanation. The guidelines recommend ferrous sulfate, fumarate, or gluconate as one tablet daily. If adverse effects occur, intake can be reduced to once every other day, or alternative oral or parenteral sources of iron can be used. Parenteral sources should be used if oral sources are contraindicated or ineffective. Treatment should be monitored and continued after hemoglobin levels are normalized (110193). Iron supplementation may also be beneficial in patients with iron deficiency without anemia, which can cause fatigue and reduced well-being, although guidelines are lacking. A meta-analysis of randomized controlled trials in adults with iron deficiency but not anemia shows that supplemental iron improves iron stores and hemoglobin levels. In addition, iron moderately reduces self-reported fatigue, but not physical capacity, when compared with placebo. Oral ferrous sulfate was used in most studies included in the analysis; however, intravenous or intramuscular iron were also used (104684). Intravenous iron has also been evaluated for the prevention of postoperative anemia. A large clinical trial in adult cardiology patients without pre-operative anemia or iron deficiency shows that a single intravenous administration of ferric carboxymaltose 1000 mg 24-72 hours before on-pump cardiac surgery reduces the number of red cell units transfused by about 5-fold, reduces the number of patients requiring transfusion by about 1.7-fold, and improves levels of hemoglobin, serum ferritin, iron, transferrin, and transferrin saturation by 4 days postoperative when compared with placebo. Additionally, improvement in hemoglobin was maintained at 6 weeks after surgery (113902).
• Pregnancy-related iron deficiency. Oral iron is effective for preventing pregnancy-related iron deficiency. Details: Clinical research shows that taking iron orally at an average daily dose of 20-225 mg of elemental iron increases maternal hemoglobin levels by up to 1 gram/dL when compared with placebo and reduces the risk of maternal anemia by 62% to 100% (20122,20123,20124,110180,110188). Some clinicians may recommend alternating days of iron administration to reduce gastrointestinal adverse effects. A pooled analysis shows that taking iron supplements on alternating days during pregnancy maintains adequate iron intake and reduces gastrointestinal adverse effects when compared with taking iron daily (96625). Various forms of oral iron seem to be equally effective for raising hemoglobin levels (110185,110188). However, in patients with anemia during pregnancy, a meta-analysis of clinical research shows that intravenous iron sucrose and ferric carboxymaltose were more effective than oral ferrous sulfate for improving hemoglobin levels (110185).

POSSIBLY EFFECTIVE

• Breath-holding attacks. Oral iron seems to be effective for reducing the frequency of breath-holding attacks in children with iron deficiency. Details: The incidence of breath-holding attacks is increased in children with iron deficiency or iron deficiency anemia. Most research shows that oral supplementation with ferrous sulfate 3-6 mg/kg daily for 4-16 weeks reduces the frequency of breath-holding attacks in children aged 1-72 months (20128,104682,104683). The best evidence comes from a meta-analysis of one randomized controlled trial and 11 observational single arm studies (104682). In this analysis, approximately 84% of children experienced at least a 50% decreased frequency of breath-holding attacks (104682). Some preliminary clinical research also shows that administering intramuscular iron reduces the frequency of breath-holding attacks and increases remission in children with iron deficiency anemia (20128).
• Cognitive function. Oral iron seems to be effective for improving cognitive function in children and adolescents with iron deficiency. Details: Taking iron orally seems to improve cognitive function in iron-deficient children and adolescents (20121,112600). For example, ferrous sulfate 650 mg twice daily for 8 weeks improved verbal learning and memory in non-anemic iron-deficient adolescent females (1095). Ferrous sulfate 50 mg twice weekly for 16 weeks appeared to improve attention measures in adolescent females with possible anemia (91186). Iron also appears to reverse developmental and learning deficits caused by iron-deficiency in anemic infants (1104). Some clinical research is focused on children and adolescents from low- and middle-income countries. In children aged 5-19 years with or without iron-deficiency anemia, a meta-analysis of clinical research shows that iron supplementation for 3-8 months dose-dependently improves measured intelligence by a modest amount. However, there was no effect on other measures of cognition, including attention or memory (110181). Another meta-analysis of clinical research in school age children shows that taking iron for 2-12 months modestly improves intelligence, attention, and memory, but not educational achievement, when compared with placebo or no intervention. However, sub-analyses show that any benefits are limited to children with anemia (112600). Most studies included in the analyses evaluated daily iron supplementation, with a few studies assessing iron taken 4-6 times weekly (110181,112600). In contrast, a large clinical trial in schoolchildren in Ethiopia shows that taking iron supplements, providing 42 mg of elemental iron, once weekly for 11 months does not improve working memory, nonverbal intelligence, planning, or problem-solving, and may even worsen one measure of attention and concentration when compared with placebo (113904). These discrepant findings may be related to differences in frequency of dosing (daily vs. weekly) and baseline demographics; only 20% and 4% of children in this study had iron deficiency and iron deficiency anemia, respectively.
• Heart failure. Intravenous iron seems to be effective for improving recovery in patients with heart failure and iron deficiency. It is unclear if oral iron is effective. Details: Iron deficiency is common in patients with heart failure (17499,112597,112598,112599). A number of large clinical trials and meta-analyses of clinical research in patients with heart failure show that administering intravenous iron, as ferric carboxymaltose, iron dextran, iron isomaltoside, or iron sucrose, for at least 12 weeks modestly improves quality of life, increases exercise capacity, and reduces hospitalizations when compared with placebo or standard care. However, there was no effect on all-cause mortality or cardiovascular mortality (17498,91179,110176,110187,112597,112598,112599,113900,113901). A meta-analysis of 3 large clinical trials in patients with heart failure shows that ferric carboxymaltose, administered intravenously at baseline and then 6 weeks or 6 months later, reduces the rate heart failure-related hospitalizations by 16% when compared with placebo (113901). Some individual clinical trials have used intravenous ferric carboxymaltose 200 mg or iron sucrose 200 mg in patients with mild or moderate heart failure and iron deficiency (17498,91179) while others administered 1500 mg every 6 months (113900,113901). Guidelines from the British Society of Gastroenterology suggest that treatment with parenteral iron improves symptoms and quality of life in patients with functional iron deficiency related to CHF (110193). Limited research has investigated the effect of oral iron in this population. A small meta-analysis of clinical research shows with low certainty that taking iron orally has beneficial effects on serum ferritin and left ventricular ejection fraction (110178). Most research shows that taking oral iron does not improve hemoglobin levels, quality of life, or exercise capacity when compared with placebo (100970,110178). However, one small clinical trial shows that taking oral iron modestly improves iron status and overall symptoms and increases the 6-minute walking distance by about 46 meters, compared with a reduction of only 14 meters in those taking placebo (110183). Some doses used in individual clinical studies have included iron polysaccharide 150 mg twice daily for 16 weeks and ferrous sulfate 200 mg three times daily for 12 weeks (100970,110183).
• Restless legs syndrome (RLS). Oral and intravenous iron seem to be beneficial for RLS. The American Academy of Neurology recommends a combination of oral ferrous sulfate and vitamin C or intravenous ferric carboxymaltose for patients with RLS. Details: RLS is commonly associated with iron deficiency anemia. Some clinical research shows that taking iron in the form of ferrous sulfate 325 mg twice daily for 12 weeks reduces RLS symptoms comparably to pramipexole. Symptoms such as leg discomfort, need to move, and sleep disturbances improved considerably in about half of the patients taking either treatment (91181). Additional clinical research shows that taking ferrous sulfate 325 mg twice daily along with vitamin C 100 mg twice daily for 12 weeks reduces symptoms of RLS when compared with vitamin C alone in patients with RLS and low-normal serum ferritin levels (94189). Based on these results, clinical practice guidelines by the American Academy of Neurology report that taking this combination of oral ferrous sulfate and vitamin C is likely to improve symptoms in patients with RLS and low-normal serum ferritin (93587). Intravenous iron may also reduce symptoms of RLS. Clinical practice guidelines by the American Academy of Neurology report that two doses of intravenous ferric carboxymaltose 500 mg given 5 days apart are likely to improve symptoms and quality of life within 28 days in patients with moderate to severe RLS, regardless of serum ferritin levels. Intravenous iron sucrose has also been evaluated in patients with RLS, but there is currently insufficient available evidence to support or refute the use of this form of iron for treating RLS (93587).

POSSIBLY INEFFECTIVE

• Athletic performance. Oral iron does not seem to improve athletic performance. Details: A meta-analysis of clinical research in adults of childbearing age shows that iron supplementation improves some exercise performance measures, such as maximal oxygen uptake capacity, but not others, such as time until exhaustion and energy consumption, when compared with control (91184). Another meta-analysis of clinical research in patients with iron deficiency without anemia shows that iron supplementation improves subjective measures of fatigue, but does not improve exercise time to exhaustion or other measures of physical capacity (104684). A small clinical study in healthy children shows that taking iron supplements or consuming food providing iron 30-200 mg daily for 1-2 months improves running performance when compared with placebo. This was demonstrated by reductions of heart rate of 6.6 to 8 beats per minute during the running exercise. One preliminary study included in this analysis also showed that iron supplementation improved treadmill endurance time (20140).
• Child growth. Oral iron does not seem to be beneficial for child growth. Details: Meta-analyses of mainly preliminary clinical research show that oral iron supplementation, at doses averaging 2-80 mg or 1-10 mg/kg elemental iron daily for up to 52 weeks, does not increase growth rate in children (20131,20132,20133,95434).
• Preterm labor. Oral iron does not seem to prevent preterm labor and may actually increase the risk in malaria-endemic regions. Details: A meta-analysis of results from five clinical studies shows that maternal intake of iron as ferrous sulfate 20-60 mg daily for 14-26 weeks starting in the second trimester of pregnancy does not affect the length of gestation or increase birthweight of the infant (95434). In females from a malaria-endemic area who have never been pregnant before, another clinical study shows that taking ferrous gluconate 60 mg and folic acid 2.8 mg weekly, starting before conception and continuing to the first antenatal visit, may more than double the risk of preterm birth, defined as a delivery under 37 weeks gestation, when compared with folic acid alone (100969). Some research suggests that the adverse outcome in this latter study may be explained by a rise in hepcidin levels in pregnant patients with malaria. Hepcidin is a hormone that regulates iron absorption and distribution, and malaria can upregulate hepcidin. High levels of hepcidin can decrease iron absorption, stimulate inflammatory processes, and cause progesterone withdrawal, leading to preterm labor (102863).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• ACE inhibitor-induced cough. It is unclear if oral iron is beneficial in patients with this condition. Details: A small clinical trial shows that taking ferrous sulfate 256 mg daily reduces or eliminates cough induced by ACE inhibitors such as captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril), and others, when compared with placebo (7307).
• Androgenic alopecia. Oral iron has only been evaluated in combination with other ingredients, its effect when used alone is unclear. Details: A moderate-sized clinical study in adults with androgenic alopecia or telogen effluvium shows that taking one tablet daily of a specific product (GFM Oral, Cantabria Labs), providing an unknown dose of iron in combination with selenium, taurine, cysteine, methionine, and hydrolyzed collagen, along with conventional therapy, consisting primarily of finasteride or minoxidil, for 12 weeks improves hair loss when compared with conventional therapy alone (111636). It is unclear if this effect is due to iron, other ingredients, or the combination.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral iron is beneficial in children with ADHD. Details: Three small clinical studies in children with ADHD and iron deficiency shows that taking oral iron improves some measures of ADHD after 1-3 months of treatment when compared with baseline or placebo. These studies used ferrous sulfate 5 mg/kg daily, ferrous sulfate 80 mg daily, ferrous fumarate 200 mg daily for children weighing up to 30 kg, or ferrous fumarate 400 mg daily for children weighing more than 30 kg (1093,16013,110191).
• Child development. It is unclear if oral iron is beneficial for improving development in non-anemic children. Details: Some observational research has found that iron deficiency in infancy is associated with poor verbal performance and social skills in childhood (102862). It is unknown whether iron supplementation can ameliorate these developmental issues. In non-anemic infants and children, preliminary clinical research shows that iron does not improve cognitive performance; the evidence for the benefits of iron on psychomotor development is conflicting (20129,20130,91315,96616,96626).
• Esophageal cancer. It is unclear if oral iron is beneficial for esophageal cancer prevention. Details: Population research has found that taking iron supplements is associated with a 32% lower risk of esophageal adenocarcinoma when compared to never taking iron supplements. However, use of iron supplements is not associated with a lower risk of esophageal squamous cell carcinoma (95435).
• Fatigue. It is unclear if oral iron is beneficial in patients with fatigue due to iron deficiency without anemia. Details: A meta-analysis of mainly preliminary clinical research in adults with iron deficiency without anemia shows that iron reduces self-reported fatigue moderately more than placebo (104684). A specific ferrous sulfate supplement (Tardyferon; Pierre Fabre Médicament) providing 80 mg of elemental iron daily for 4-12 weeks was used in two studies included in this analysis (11406,91188).
• Inflammatory bowel disease (IBD). In patients with active IBD, intravenous iron may be more beneficial than oral iron due to impaired absorption. However, it may also increase the risk of infection in these patients. Details: Since the absorption of oral iron may be impaired in patients with active symptoms of IBD, guidelines from the British Society of Gastroenterology suggest that treatment with parenteral iron may be needed in patients with IBD who have moderate to severe iron-deficiency anemia (110193). However, a meta-analysis of clinical research in this population shows that administering IV iron, usually as iron sucrose or ferric carboxymaltose, increases the risk of infection by 73% when compared with oral iron or no iron (110186).
• Postoperative recovery. It is unclear if intravenous iron is beneficial for recovery following cardiac surgery. Details: A meta-analysis of low- to moderate-quality clinical research in patients with preoperative iron-deficiency anemia shows that treatment with intravenous iron before cardiac surgery does not improve the rate of transfusions or the length of stay in the intensive care unit or hospital when compared with control groups, including placebo, oral iron, or no treatment. Also, a meta-analysis of clinical research shows that intravenous iron does not reduce postoperative mortality rates (110182).
• Postpartum depression. Although there has been interest in using iron for postpartum depression, there is insufficient reliable information about the clinical effects of iron for this condition.
• Prematurity. Enteral iron seems to be beneficial for some measures of development in preterm infants. Details: A meta-analysis of clinical research in preterm or low birthweight infants fed human milk shows that enteral iron supplementation increases linear growth and reduces the risk of anemia when compared with control groups receiving no iron supplementation. However, there was no effect on serum ferritin, weight, head circumference, cognitive development, risk of infection, or risk of necrotising enterocolitis (110177). Additional clinical research in infants born at 24-28 weeks' gestation shows that a higher average enteral iron dose by 60 days of age is positively associated with cognitive performance at 2 years of corrected age. However, this association was not present for iron doses received at 90 days of age (110190). More evidence is needed to rate iron for these uses.

(Read more about IRON)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Androgenic alopecia. Oral L-cysteine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in adults with androgenic alopecia or telogen effluvium shows that taking a combination product containing L-cysteine (dose not specified), hydrolyzed collagen, taurine, methionine, iron, and selenium (GFM Oral, Cantabria Labs) daily along with conventional therapy, consisting primarily of finasteride or minoxidil, for 12 weeks improves hair growth when compared with conventional therapy alone (111636). It is unclear if this effect is due to L-cysteine, other ingredients, or the combination.
• Cancer. Although there is interest in using oral L-cysteine for prevention of cancers of the upper gastrointestinal tract, there is insufficient reliable information about the clinical effects of L-cysteine for this purpose.
• Diabetes. Although there is interest in using oral L-cysteine for diabetes, there is insufficient reliable information about the clinical effects of L-cysteine for this condition.
• Erythropoietic protoporphyria (EPP). Although there is interest in using oral L-cysteine for EPP, there is insufficient reliable information about the clinical effects of L-cysteine for this condition.
• Gastritis. It is unclear if oral L-cysteine is beneficial for gastritis. Details: A moderate-sized, single center, non-randomized study in adults with chronic atrophic gastritis (CAG) shows that taking L-cysteine (Acetium, Biohit) 300 mg daily for 2 years improves gastrointestinal symptom scores. Patients reported an approximate 2 to 3-point improvement on a 10-point visual analog score (VAS) and global symptomatic score (GSS) compared to a less than 0.3 point improvement in the control group. The most significant reduction was observed during the first 3 months of therapy. While these improvements were statistically significant compared to baseline, statistical analysis between groups was lacking (115479).
• Hangover. Oral L-cysteine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial shows that an immediate release product (Catapult Cat L-cysteine vitamin tablet) providing L-cysteine 1200 mg in combination with other ingredients, taken six times between 7 pm and midnight in conjunction with alcohol 1.5 grams/kg over 3 hours, modestly reduces symptoms of hangover, including nausea, headache, stress, and anxiety, when compared with placebo. Each L-cysteine tablet also contained thiamine 50 mg, riboflavin 1.4 mg, niacin 16 mg, vitamin B6 1.4 mg, biotin 50 mcg, folic acid 200 mcg, vitamin B12 2.5 mcg, and vitamin C 80 mg (109709). Other researchers have questioned the validity of the statistical methods used in this study and suggest that not all of the noted outcomes were statistically significant (109716).
• Photoreactive keratectomy. It is unclear if oral L-cysteine is beneficial for promoting wound healing after photoreactive keratectomy. Details: Preliminary clinical research shows that taking L-cysteine 100 mg twice daily for 14 days starting one week before photoreactive keratectomy reduces complete corneal healing time by about 2 days when compared with taking placebo (109727).
• Venous leg ulcers. Topical L-cysteine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial shows that topical application of a cream containing L-cysteine 2 mg/gram, glycine 10 mg/gram, and D,L-threonine 1 mg/gram for 12 weeks modestly increases healing and decreases pain when compared with placebo. However, there was no difference in exudate, offensive smell, or granulation. The cream was used as part of a treatment regimen involving cleaning and bandaging, two to five days each week (10255).
• Smoking cessation. It is unclear if oral L-cysteine is beneficial for promoting smoking cessation. Details: Preliminary clinical research shows that use of a slow-release lozenge containing L-cysteine 3 mg (Acetiumlozenge; Biohit Oyj) with each cigarette for 6 months does not increase the odds of smoking cessation when compared with placebo (109714). However, this study may have been inadequately powered to detect a difference between groups. An adequately powered study by the same research group shows that using this lozenge increases the odds of smoking cessation by about 51% when compared with placebo (109710).
• Stroke. Although there is interest in using oral L-cysteine for stroke prevention, there is insufficient reliable information about the clinical effects of L-cysteine for this purpose. More evidence is needed to rate L-cysteine for these uses.

(Read more about L-CYSTEINE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Lemon has only been evaluated in combination with quince in a nasal spray for hay fever; its effect when used alone is unclear. Details: A small clinical study in patients with grass pollen allergy shows that using a specific nasal spray (Gencydo, Weleda AG) containing lemon and quince three times daily for 7 days does not improve the symptoms of allergic rhinitis when compared with placebo. In this study, using the nasal spray reduced airway resistance during inspiration at 10 and 20 minutes after pollen exposure, and reduced airway resistance during expiration at 20 minutes after pollen exposure (98826).
• Anxiety. It is unclear if aromatherapy with lemon essential oil reduces anxiety. Details: A small clinical study in first year nursing students in Turkey shows that administering aromatherapy with lemon essential oil for 15 minutes prior to an exam reduces test anxiety scores when compared with control students (110779). However, it is unclear whether any improvements are clinically significant or lead to improved test scores. Lemon oil has also been evaluated in pregnancy. A small clinical trial in Turkey in pregnant adults in active labor shows that administering aromatherapy with lemon oil, 1 drop placed on a cotton ball, every hour until delivery does not reduce anxiety when compared with control (115746).
• Halitosis. Lemon essential oil has only been evaluated in combination with other essential oils; its effect when used alone is unclear. Details: Preliminary research in males with dementia in a long-term care facility shows that cleaning the tongue, gums, and teeth with a solution of lemon, peppermint, and tea tree essential oils twice daily for 7 days improves oral condition, measured on the Korean Oral Assessment Guide scale, increases salivary pH into the normal range, and decreases halitosis score when compared with saline control. On a scale of 0 to 5, the essential oil mixture reduced the halitosis score by 1.24 points, compared with 0.2 points for the control (112957).
• Hypertension. It is unclear if oral lemon is beneficial in patients with high blood pressure. Details: A small, prospective, population study in middle-aged Japanese women has found that increased lemon intake is associated with a modest reduction in systolic, but not diastolic, blood pressure (93471).
• Kidney stones (nephrolithiasis). It is unclear if oral lemon juice is beneficial for recurrent idiopathic calcium oxalate nephrolithiasis. Details: A randomized, controlled trial in patients with recurrent idiopathic calcium oxalate nephrolithiasis shows that taking fresh lemon juice 60 mL orally twice daily for 2 years with a standard diet does not improve the time to stone recurrence when compared with no supplementation. The validity of these findings is limited due to poor patient adherence, which declined from 79% at 6 months, to 68% at 1 year, and 48% at 2 years. When restricted to a 1-year follow-up, stone recurrence occurred in 10% of patients taking lemon juice, compared with 21% of patients in the control group; this difference was statistically significant (107489).
• Labor pain. It is unclear if aromatherapy with lemon oil is beneficial for labor pain. Details: A small clinical trial in Turkey in pregnant adults in active labor shows that administering aromatherapy with lemon oil, 1 drop placed on a cotton ball every hour until delivery, modestly reduces patient-reported pain during the early phase (cervical dilation 5-7 cm) when compared with control (115746). However, clinical significance is unclear, and pain is not reduced during the later phase of active labor (cervical dilation 8-10 cm).
• Meniere disease. Although there is interest in using lemon orally for Meniere disease, there is insufficient reliable information about the clinical effects of lemon for this condition.
• Myocardial infarction (MI). It is unclear if aromatherapy with lemon essential oil is beneficial in patients with acute MI. Details: A small clinical study in hospitalized patients with acute MI shows that administering aromatherapy with lemon essential oil over 3 days moderately reduces systolic blood pressure, but not diastolic blood pressure, when compared with a paraffin control. Heart rate and anxiety were reduced by a small amount the day following the completion of lemon aromatherapy (103455).
• Nausea and vomiting. It is unclear if aromatherapy with lemon oil is beneficial in palliative care patients with nausea and vomiting. Details: A small observational study in hospitalized palliative care patients with advanced cancer has found that administering aromatherapy with lemon oil pads relieves nausea and vomiting in 73% of applications (110778). The interpretation of these findings is limited by the use of a retrospective chart review and the lack of a comparator group.
• Obesity. Although there is interest in using lemon orally for obesity, there is insufficient reliable information about the clinical effects of lemon for this condition.
• Oral mucositis. Lemon has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A randomized, controlled trial in patients with head and neck cancer receiving external beam radiotherapy 5 days weekly shows that using a 2:1 oral honey-lemon throat spray four to eight times daily, beginning 1 day prior to radiotherapy initiation and continuing for 5 weeks, does not improve severity of mucositis when compared with oral benzydamine hydrochloride throat spray applied four to eight times daily. The actual rate of oral mucositis occurrence is 65% in those receiving the honey-lemon spray, compared with 35% with the benzydamine hydrochloride spray; however, this difference was not statistically significant (107487). This study may have been inadequately powered to detect a difference between groups. Also, the validity of these findings is limited due to the lack of objective outcome measures.
• Postoperative nausea and vomiting (PONV). It is unclear if aromatherapy with lemon essential oil is beneficial in patients with PONV. Details: Preliminary research in patients undergoing lower extremity fracture surgery shows that aromatherapy with lemon essential oil started the morning of surgery, then every 2 hours to the end of surgery, in the recovery room, and 16 hours after surgery reduces the frequency, severity, and amount of PONV, and the frequency of anti-emetic drug administration after surgery, when compared with control. The intensity of pain is also reduced, but not the amount of post-operative opioid needed (112956).
• Pregnancy-induced nausea and vomiting. It is unclear if aromatherapy with lemon essential oil is beneficial in patients with nausea and vomiting due to pregnancy. Details: A small clinical study in pregnant patients shows that practicing aromatherapy with 2 drops of lemon essential oil placed on a cotton ball as needed modestly reduces pregnancy-induced nausea and vomiting on 2 of 4 days of the study when compared with placebo (93475).
• Radiation-induced sialadenitis. Aromatherapy with lemon essential oil has only been evaluated in combination with other essential oils; its effect when used alone is unclear. Details: A small clinical study in patients with thyroid cancer shows that receiving 10-minute aromatherapy baths with lemon and ginger essential oils prior to meals for 2 weeks before treatment with radioactive iodine therapy attenuates damage to the salivary gland when compared with distilled water baths (98129).
• Respiratory tract infections. Although there is interest in using lemon orally for respiratory tract infections such as cold and flu, there is insufficient reliable information about the clinical effects of lemon for these conditions. More evidence is needed to rate lemon for these uses.

(Read more about LEMON)

EFFECTIVE

• Bowel preparation. Various magnesium salts are used for cleansing the bowel prior to procedures such as colonoscopy. Details: Various magnesium salts, including citrate, hydroxide, oxide, and sulfate, are ingredients in bowel preparation products available over-the-counter or by prescription only.
• Constipation. Magnesium salts are effective when used short-term orally to treat constipation and chronic idiopathic constipation (CIC). Details: Magnesium citrate, hydroxide, oxide, and sulfate salts are commonly used as laxatives. Magnesium citrate 11.3-17.45 grams has been used; magnesium hydroxide 2.4-4.8 grams, as 30-60 mL of milk of magnesia, has also been used (113483,113484). Magnesium sulfate, also known as Epsom salt, which seems to have the most potent effect, has been used as 10-30 grams (6430,113485). Magnesium salts should only be used for occasional treatment of constipation, and doses should be taken with a full 8-ounce glass of water. Magnesium oxide seems to be beneficial in adults with CIC when taken short-term. Clinical guidelines published by the American Gastroenterology Association and American College of Gastroenterology in 2023 give a conditional recommendation suggesting the use of magnesium oxide over managing CIC without magnesium oxide based on low-quality studies conducted over 4 weeks. The recommended starting dose is 400-500 mg daily with dose titration per symptom response and side effects (112859). A small clinical study in patients with CIC who are not taking chronic medications shows that taking magnesium oxide 1.5 grams in three divided doses daily for 28 days increases spontaneous bowel movements when compared with placebo (104397). It is unknown if magnesium is beneficial for CIC when used long-term.
• Dyspepsia. Magnesium salts are effective when used orally as antacids. Details: Magnesium carbonate, hydroxide, oxide, or trisilicate salts are used orally as antacids to reduce symptoms of gastric hyperacidity or gastroesophageal reflux. Magnesium hydroxide has the fastest onset of action. The onset for magnesium carbonate is slower due to its crystal structure. Magnesium trisilicate has the slowest onset and longest duration of action due to poor solubility (6844). Doses used include magnesium hydroxide 400-1200 mg (5-15 mL of milk of magnesia) up to four times daily, or magnesium oxide 800 mg daily (15).
• Eclampsia. Magnesium sulfate is considered the drug of choice for control of seizures. Details: Intravenous (IV) and/or intramuscular (IM) magnesium sulfate is considered the agent of choice for seizure prophylaxis during eclampsia by the American College of Obstetricians and Gynecologists (ACOG) (15,12591,12592,61012,61184). Typical doses include 4-6 grams of magnesium sulfate by IV infusion in 250 mL of dextrose 5% or normal saline solution, followed by 4-5 grams of magnesium sulfate IM every 4 hours, or 1-3 grams per hour by continuous IV infusion. Doses should be adjusted according to serum levels and urinary excretion, and should not exceed 30-40 grams of magnesium sulfate daily (15,12591). Meta-analyses of clinical research show that treatment with IV or IM magnesium reduces the risk of seizure recurrence by 33% to 69% when compared with phenytoin, and by 47% to 60% when compared with diazepam (19960,60818,60954,60964,61105). One preliminary clinical study shows that lower doses of IV magnesium sulfate (9 grams loading dose and maintenance of 2.5 grams every 4 hours for 24 hours) are as effective as higher doses (14 grams loading dose and maintenance of 5 grams every 4 hours for 24 hours) for reducing the recurrence of eclamptic seizures (89383). It is generally recommended that treatment be continued for at least 24 hours after the last seizure (15). Oral magnesium has not been evaluated for eclampsia.
• Hypomagnesemia. Hypomagnesemia can be effectively treated with oral or parenteral magnesium. Details: Taking magnesium orally or parenterally is helpful for treating and preventing hypomagnesemia associated with alcoholism, cirrhosis of the liver, congestive heart failure (CHF), severe or prolonged diarrhea or vomiting, kidney dysfunction, inflammatory bowel disease (IBD), pancreatitis, malabsorption syndromes, and other conditions (6280,6281,8088,8089). The dose and salt of magnesium for oral replacement therapy should be chosen carefully to avoid causing diarrhea. The gluconate and chloride salts cause less diarrhea, while the oxide salt is more likely to cause diarrhea and should be avoided. Magnesium chloride should also be avoided due to poor solubility which decreases absorption (6430,8099,10664). Orally, magnesium sulfate 3 grams every 6 hours for four doses has been used for hypomagnesemia (15). Parenteral magnesium doses must be individualized according to serum magnesium levels, but a typical starting dose for mild deficiency is 1 gram of magnesium sulfate intramuscularly (IM) every 6 hours for 4 doses (15). For more severe deficiency, 5 grams of magnesium sulfate may be given as an intravenous (IV) infusion in 1 liter of dextrose 5% or normal saline solution over 3 hours (15).
• Pre-eclampsia. Magnesium sulfate is considered the drug of choice for seizure prophylaxis in patients with pre-eclampsia. Details: Intravenous (IV) and/or intramuscular (IM) magnesium sulfate is considered the agent of choice for seizure prophylaxis during pre-eclampsia by the American College of Obstetricians and Gynecologists (ACOG) (12591,12592,61012,61184). Some meta-analyses show that IV administration of magnesium sulfate reduces the risk of eclampsia when compared with placebo, phenytoin, or diazepam in patients with pre-eclampsia (19960,60818,60960,60979). A typical initial dose is 4-5 grams of magnesium sulfate by IV infusion in 250 mL of dextrose 5% or normal saline solution, followed by 4-5 grams of magnesium sulfate IM every 4 hours, or 1-3 grams of magnesium sulfate per hour by continuous IV infusion. Doses should be adjusted according to serum levels and urinary excretion, and should not exceed 30-40 grams of magnesium sulfate daily (15,12591). The optimal duration of prophylaxis has not been determined. A meta-analysis suggests that using a shorter duration of 12 hours or less is not associated with an increase in risk of eclamptic seizures when compared with regimens of 24 hours or longer (108732). However, studies are likely underpowered due to the low incidence of eclampsia. Oral magnesium has been evaluated for the prevention of pre-eclampsia in healthy adults, but taking magnesium citrate 300 mg daily, starting at 12-20 weeks' gestation and continuing until delivery, does not reduce the incidence of pre-eclampsia when compared with placebo (103724).

LIKELY EFFECTIVE

• Cerebral palsy. Most evidence shows that antenatal magnesium reduces the risk of cerebral palsy in preterm infants, although there are some inconsistent results. Details: Most clinical studies and meta-analyses show that antenatal magnesium sulfate reduces the risk of cerebral palsy by about 32% and the risk of motor dysfunction by about 45% in preterm infants (60915,60927,60931,61001,97485,103734,103754,114675,114681). The lowest effective dose of magnesium sulfate seems to be 4 grams intravenously, with or without a maintenance dose of 1 gram/hour until birth or for 24 hours. In obese females, a higher dose, based on body weight, may be needed (97485,97495,103734,103754). However, some studies have inconsistent results (8093,19998,98293,98295,112784). Giving females at risk of imminent preterm birth (prior to 32 weeks), intravenous magnesium sulfate 4.5 grams over 20 minutes followed by 1 gram per hour until birth or for 24 hours, in addition to a standard treatment protocol, does not reduce the incidence of cerebral palsy (112784). Oral magnesium has not been evaluated for this purpose.
• Seizures. Intravenous magnesium sulfate is used for treating seizures of various etiologies. Details: Intravenous magnesium sulfate may be useful for controlling seizures associated with epilepsy, glomerulonephritis, hypothyroidism, and acute nephritis in children (15). Oral magnesium has not been evaluated for this purpose.
• Torsades de pointes. Intravenous magnesium sulfate is the first-line treatment for torsades de pointes after measures to correct precipitating factors have been unsuccessful. Details: Intravenous magnesium sulfate has been used successfully to treat the life-threatening ventricular tachycardia, torsades de pointes (15,6844). The Advanced Cardiac Life Support (ACLS) guidelines of the American Heart Association recommend a dose of 1 to 2 grams diluted in 50-100 mL Dextrose 5% solution given IV over 5-60 minutes, followed by a continuous IV infusion of 0.5-1 gram/hour.

POSSIBLY EFFECTIVE

• Arrhythmia. Magnesium sulfate is effective for the specific type of ventricular tachycardia known as torsades de pointes, and seems to be helpful for treating other types of arrhythmias. Evidence for the role of oral or intravenous magnesium in preventing postoperative arrhythmias is conflicting. Details: Administering magnesium intravenously or orally may be helpful for treating atrial and ventricular tachycardia and fibrillation, and supraventricular tachycardia (9497,13352,13354,13355,13356,60804,60829,60877,61113,111696). Arrhythmias associated with congestive heart failure have been treated with magnesium sulfate 8 grams infused over 12 hours (9497). For rate control in atrial fibrillation, magnesium sulfate 2.5 grams IV over 20 minutes, followed by 2.5 grams IV over 2 hours has been used (13356). For paroxysmal supraventricular tachycardia, single doses of 1-4 grams of magnesium chloride have been used (13352). For atrial tachycardia, 2 grams of magnesium sulfate in 10 mL of dextrose 5% solution has been given IV over 1-10 minutes, followed by 5-10 grams of magnesium sulfate in 250-500 mL dextrose 5% solution as an IV infusion over 5 hours (13354,13355). Research on the effects of intravenous magnesium for preventing arrhythmias after cardiac surgery is conflicting. Some meta-analyses show that intravenous magnesium reduces the risk of atrial fibrillation, ventricular arrhythmias, or supraventricular arrhythmias following cardiac surgery by 23% to 48% when compared with placebo (60814,60826,60828,60838,61008,61033,61181,97487,97490). Doses of magnesium sulfate used include 30 mg/kg in 500 mL normal saline (97490), or 80-100 mg/kg added to the cardioplegia solution (97487). Also, one small study in adults after CABG surgery suggests that taking magnesium hydroxide 1600 mg orally reduces arrhythmia as effectively as receiving magnesium sulfate 2000 mg intravenously (99315). However, other meta-analyses that only include higher-quality trials show that magnesium supplementation does not reduce the risk of ventricular or supraventricular arrhythmias following cardiac surgery (61010,61024,61031,105081). A meta-analysis of clinical trials of intravenous magnesium for prevention of new-onset atrial fibrillation after non-cardiac surgeries shows that it does not reduce the incidence significantly when compared with placebo (112778). However, there was a high risk of bias in the analysis, and variability in types of surgery, and the salt and dose of magnesium used.
• Asthma. Parenteral magnesium sulfate can help to reverse severe acute asthma attacks and reduce the need for hospital admission. It is unclear if nebulized magnesium is beneficial for acute asthma attacks. However, oral magnesium does not seem to be beneficial. Details: Overall, a single dose of intravenous magnesium seems to improve pulmonary function in acute asthma exacerbation and reduce the risk of hospitalization, particularly in patients with severe asthma, and those who have failed initial treatment with nebulized albuterol and intravenous corticosteroids (60888,90023,96483,104398,107365). The typical dose used for adults is 2 grams of magnesium sulfate infused over 20 minutes (15). For children, 25-75 mg/kg, to a maximum of 2 grams, infused over 20-30 minutes has been used (15,96483,107365). However, a post-hoc analysis of one large clinical trial (104400) designed to assess nebulized magnesium in children with acute asthma has found that adding IV magnesium to nebulized magnesium is associated with greater odds of hospitalization when compared with no IV magnesium (105919). This post-hoc analysis did not differentiate between precautionary and necessary hospitalizations. Although some clinical research and a meta-analysis in patients with acute asthma exacerbation show that nebulized magnesium in combination with standard treatment improves airway function, respiratory rate, and clinical asthma severity when compared with standard treatment alone, it is unclear whether these findings are clinically relevant (90016,113466). Most evidence, including larger clinical trials and meta-analyses, has not shown benefit of adjunct nebulized magnesium for acute asthma in adults or children (60888,90002,96484,104400,105920,113466,114674). Oral magnesium also does not seem to be beneficial. A meta-analysis of small clinical trials in children and adults with asthma shows that taking magnesium supplements orally does not improve lung function or reduce bronchodilator use when compared with control (104404).
• Colorectal cancer. Increasing dietary magnesium intake seems to lower the risk of colon cancer but not rectal cancer. Details: Epidemiological research shows that increased dietary magnesium intake is associated with a reduced risk of colon cancer, but the risk of rectal cancer is not affected (89387,90017,90027,101355).
• Diabetes. Low dietary magnesium may increase the risk of developing type 2 diabetes, but evidence on the use of supplements for treating type 2 diabetes is conflicting. Details: Higher dietary magnesium intake is associated with lower fasting insulin concentrations and a reduced risk of developing type 2 diabetes in adults and obese children (13369,15548,96473,97486,98294,103736,105918,106920). In people with existing type 2 diabetes, hypomagnesemia is found in 25% to 38% of patients, especially in those with poorly controlled diabetes (1172). Population research in adults with type 2 diabetes also shows that a dietary magnesium intake of less than 250 mg daily is associated with a 56% higher risk of mortality. Preliminary subgroup analyses suggest that the risk of mortality is higher in those with glycated hemoglobin (HbA1C) levels above 7% (110051). A meta-analysis of small, heterogeneous clinical studies in adults with type 2 diabetes suggests that magnesium may modestly reduce HbA1C in patients with hypomagnesemia, but not in patients with normal magnesium levels, when compared with control (105075). Individual clinical studies using magnesium supplements in patients with type 2 diabetes or insulin resistance have shown mixed results. Some research suggests magnesium supplements can decrease fasting blood glucose and improve insulin sensitivity, as well as reduce the risk of developing diabetes in high-risk patients (10664,12582,13376,60854,99313,106920), but other research shows no effect (1171,1172,13379,13380,112780). Discrepancies in these findings might reflect differences in magnesium salts and doses used, or differences in baseline magnesium status in study subjects.
• Hypercholesterolemia. Magnesium may help improve lipid levels by a small amount in people with this condition. Details: There is some evidence that taking magnesium oxide 1 gram orally daily for 6 weeks can produce small decreases in low-density lipoprotein (LDL) and total cholesterol levels, and small increases in high-density lipoprotein (HDL) levels in patients with hypercholesterolemia. However, magnesium does not seem to improve lipoprotein (a) levels (1193). Magnesium may also lower triglycerides in people with hypertriglyceridemia (97494).
• Metabolic syndrome. Low dietary and serum levels of magnesium seem to be associated with the development of metabolic syndrome. Details: Higher magnesium intake from diet and supplements is associated with a 27% lower risk of developing metabolic syndrome in healthy females (13371) and a 31% lower risk in healthy young adults (14304). Additional epidemiological research suggests that people with low serum magnesium levels are 6-7 times more likely to have metabolic syndrome than people with normal magnesium levels (13372). In a population analysis of over 6000 individuals without metabolic syndrome at baseline, the risk of developing this condition over a 6-year follow-up period was reduced by 16% in the highest quintile of dietary magnesium intake (median intake 371 mg daily) when compared with the lowest quintile (median intake 203 mg daily). Some, but not all, research suggests that the hazard ratio for metabolic syndrome in relation to magnesium intake may be U-shaped, with higher risk at intakes below about 150 mg daily and above 600 mg daily (108963). A combination of magnesium 20 mEq daily and potassium 40 mEq daily (magnesium potassium citrate) taken orally for 16 weeks reverses metabolic side effects of chlorthalidone, such as increased fasting plasma glucose and hypokalemia, more effectively than potassium chloride 40 mEq daily alone (112932).
• Osteoporosis. Increased dietary and supplemental magnesium intake seems to increase bone mineral density and decrease bone loss in postmenopausal patients. Details: Preliminary clinical research shows that taking magnesium hydroxide orally, 300-1800 mg daily for 6 months, then 600 mg daily for 18 months, or magnesium citrate orally 1830 mg daily for 30 days, might reduce bone loss and bone turnover in postmenopausal patients with osteoporosis (9104,60928). Some epidemiological research also suggests that magnesium intake is related to increased bone mineral density (12501,12502,12503,12504,90014), although not all studies have found an association (12505,98286).
• Postoperative pain. Injectable magnesium has been used with promising results for reducing pain and the need for other analgesics postoperatively. Details: A meta-analysis of 25 clinical trials shows that intravenous (IV) magnesium sulfate, 5-50 mg/kg bolus followed by a continuous infusion of 6 mg/kg or 500 mg hourly during surgery, seems to reduce the 24-hour postoperative use of IV morphine by 24% when compared with placebo (19968). Adding IV magnesium sulfate 3.7-5.5 grams to patient-controlled analgesia for 24 hours after surgery has also been used (19968). Additionally, meta-analyses support that adjunctive IV or intrathecal administration of magnesium reduces post-operative pain scores, improves pain relief and sensory nerve block, and decreases the need for other analgesics, when compared with control (89390,90012,90015,98287,103728,114676,114677,114678). However, some data are conflicting. In a meta-analysis of 7 trials, IV magnesium was not associated with lower pain scores over the first 48 hours postoperatively. The reasons for these discrepant findings are unclear but may be explained by differences in magnesium regimens, anesthesia protocols, and surgical populations studied. Additionally, IV magnesium appears to be less effective than dexmedetomidine (105082). Two moderate-sized clinical studies in patients undergoing total knee arthroplasty in China show that adding magnesium sulfate 2.5 mg/mL to the periarticular infiltration analgesia (PIA) cocktail or administering IV magnesium sulfate 40 mg/kg before anesthesia induction then as a 15 mg/kg infusion during surgery reduces pain scores, increases comfort levels, limits and delays the use of postoperative opioids, prolongs analgesia, and reduces markers of inflammation when compared with the usual PIA cocktail or control (111181,113677). Administering magnesium intravenously also seems to be helpful for pain control after hysterectomy. A 3-gram IV bolus of magnesium sulfate followed by an infusion of 0.5 grams per hour for 20 hours has been used. Lower doses were not effective (6848). In males undergoing laparoscopic radical resection for gastrointestinal cancer, administering IV magnesium intraoperatively, as a loading dose of 40 mg/kg followed by 15 mg/kg/hour through the end of surgery, reduces postoperative catheter-related bladder discomfort and analgesic requirements, when compared with placebo (112783). However, IV magnesium might not alleviate postoperative pain in children. Two small clinical studies show that administering a magnesium IV infusion does not reduce pain when compared with saline in children after tonsillectomy or after elective strabismus surgery (98282,105077).
• Premenstrual syndrome (PMS). Taking magnesium orally seems to relieve symptoms of PMS. Details: There is some evidence that magnesium supplementation can improve symptoms, including mood changes and fluid retention, in some patients with PMS (1187,1188,6847). Doses used include magnesium oxide 333 mg daily for 2 menstrual cycles, or magnesium pyrrolidone carboxylic acid equivalent to 360 mg elemental magnesium three times daily, from the 15th day of the menstrual cycle until onset of menstrual flow (1187,1188). Taking magnesium orally in a dose of 360 mg (elemental magnesium) three times daily for 2 months seems to prevent premenstrual migraine (1186,6847). A combination of magnesium 200 mg daily plus vitamin B6 50 mg daily seems to reduce anxiety-related premenstrual symptoms, including nervous tension, mood swings, irritability, and anxiety, when compared with placebo (8555).
• Vasospastic angina. Intravenous magnesium seems to prevent coronary spasm in patients with this condition. Details: Clinical research shows that administration of intravenous magnesium sulfate 65 mg/kg infused over 20 minutes dilates coronary arteries and suppresses acetylcholine-induced coronary spasms when compared with infusion of a dextrose solution in patients with vasospastic angina (8091).

POSSIBLY INEFFECTIVE

• Altitude sickness. Taking magnesium citrate orally does not seem to reduce acute altitude sickness risk. Details: Clinical research shows that taking magnesium citrate 1200 mg daily orally in three divided doses, beginning 3 days prior to mountain ascent and continuing until mountain descent, does not reduce the risk of acute altitude sickness when compared with placebo (60801).
• Athletic performance. Taking magnesium orally does not seem to improve energy or endurance during athletic activity. Details: Most evidence suggests that taking magnesium orally doesn't increase energy and endurance during athletic activity. Magnesium oxide, aspartate, and orotate salts do not seem to improve exercise performance when used alone or in combination with potassium, vitamin B6, or zinc (2825,2826,2828,2829,2830,60751,113655).
• Bronchiolitis. Intravenous or nebulized magnesium is not beneficial in infants with this condition. Details: Clinical research shows that administering a single IV dose of magnesium sulfate 100 mg/kg to infants with acute bronchiolitis does not improve, and may actually worsen, symptoms when compared with placebo (97482). A clinical study in infants with moderate to severe bronchiolitis shows that adding nebulized magnesium sulfate 40 mg/kg to nebulized epinephrine does not reduce hospital stay or the need for ventilator or oxygen support when compared with epinephrine alone (99317). Oral magnesium has not been evaluated for this use.
• Chemotherapy-induced peripheral neuropathy. Research on the effects of intravenous infusions of magnesium and calcium for preventing oxaliplatin neurotoxicity are inconsistent, but higher quality studies seem to show no benefit. Details: Pooled analyses of cohort studies and clinical trials show that calcium and magnesium infusions can decrease the incidence of severe oxaliplatin-induced neurotoxicity (90028,90029,90031). However, when only clinical trials are considered, the infusions do not appear to be helpful (90005,90029,90031,96474,96479).
• Complex regional pain syndrome. Intravenous magnesium is not beneficial in complex regional pain syndrome type 1. Details: Clinical research shows that receiving magnesium sulfate 70 mg/kg intravenously at the rate of 25 mL/hour for 4 hours each day for 5 days does not improve pain or level of impairment when compared with placebo in patients with chronic complex regional pain syndrome type 1 (89395).
• Emergence delirium. The majority of small clinical studies in adults and children undergoing various surgeries suggest that intravenous (IV) magnesium doesn't reduce the risk of emergence delirium. However, most clinical studies in adults suggest that IV magnesium reduces emergence agitation. Details: A small clinical study in adults undergoing surgery for endovascular aortic aneurysm repair shows that administering IV magnesium 30 mg/kg as a loading dose, followed by a 10 mg/kg/hour infusion for the duration of surgery, does not improve agitation or delirium scores when compared with administering saline (111182). Similarly, a small clinical study in children ages 2-5 years undergoing elective strabismus surgery shows that administering IV magnesium during anesthesia does not seem to prevent the occurrence of emergence delirium when compared with administering saline (105077). In a meta-analysis of 8 clinical trials in children aged 2-16 years undergoing general anesthesia for oral or ophthalmic surgery, giving IV magnesium as a 30 mg/kg loading dose followed by a 10 mg/kg/hour infusion, or as a single dose of 15-30 mg/kg, does not reduce emergence delirium scores, and may actually prolong emergence times (108729). However, there is some conflicting evidence. In patients undergoing radical mastectomy, giving intraoperative magnesium sulfate 30mg/kg over 1 hour, followed by 10 mg/kg/hour until the end of surgery, reduces emergence agitation (odds ratio 0.26) when compared with placebo (112781).
• Menopausal symptoms. Oral magnesium oxide does not seem to be beneficial for menopausal hot flashes. Details: A small, low quality study in postmenopausal patients with a history of breast cancer shows that taking magnesium oxide 400-800 mg orally daily reduces hot flashes when compared with baseline (102454). However, a larger, higher quality clinical study using magnesium oxide 800-1200 mg daily did not show any benefit when compared with placebo (98290).
• Muscle cramps. Oral magnesium does not seem to improve muscle cramp frequency or intensity. Details: Meta-analyses of small clinical trials show that magnesium supplementation for 3-6 weeks does not decrease the frequency or intensity of skeletal muscle cramps, whether the cramps are idiopathic or due to liver cirrhosis or pregnancy, when compared with placebo (90022,104395).
• Sickle cell disease. Intravenous magnesium does not add any benefit to standard therapy for sickle cell disease in children. Details: Clinical research shows that giving magnesium sulfate 40-100 mg/kg (maximum of 2 grams per dose) intravenously every hour for 6-8 doses as an adjunct to standard therapy does not decrease hospital stay, pain, or opioid use, or improve quality of life, when compared with standard therapy and placebo in children with sickle cell disease (89399,98283,101356). Oral magnesium has not been evaluated for this purpose.
• Stillbirth. Magnesium administered during pregnancy does not reduce stillbirth risk. Details: A meta-analysis of clinical research shows that magnesium supplementation does not significantly decrease the risk of stillbirths when administered during pregnancy (60925,60978).
• Tetanus. Intravenous magnesium sulfate does not seem to improve outcomes in patients with this condition. Details: A meta-analysis of clinical research shows that intravenous magnesium sulfate does not reduce mortality when compared with placebo or diazepam in patients with tetanus (61020). While some research shows that magnesium reduces the duration of hospitalization and the need for ventilation when compared with diazepam (61170), magnesium does not seem to improve these outcomes when compared with placebo (60860).
• Traumatic brain injury (TBI). Magnesium does not improve clinical outcomes in patients with moderate to severe TBI. Its effect in patients with concussions is unclear. Details: A meta-analysis of four clinical trials shows that treatment with magnesium does not significantly improve neurological outcomes or reduce the risk of mortality when compared with placebo in patients with moderate to severe TBI (60905). A small observational cohort study in adolescents with concussions has found that adding oral magnesium 400 mg twice daily for 5 days to standard treatment with acetaminophen and ondansetron is associated with a trend toward reduced symptom severity when compared with standard treatment alone (104401). The validity of this study is limited by its observational nature and small cohort size.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. Intravenous magnesium does not seem to help reduce symptoms of alcohol withdrawal but may reduce the duration of alcoholic delirium. Details: Preliminary clinical research shows that administration of four intramuscular injections of magnesium sulfate 2 grams at 6-hour intervals does not reduce symptoms of alcohol withdrawal when compared with saline (61063). A small observational study in patients with alcoholic delirium has found that administering magnesium sulfate IV 50 mg/kg every 8 hours, in addition to usual sedation, is associated with a reduction of delirium by approximately 2 days, or 4 days when given every 12 hours in addition to dexmedetomidine, when compared with usual sedation alone (111180). However, half of patients had hypomagnesemia at baseline; it is unclear if effects would be similar for patients with normal magnesium levels. Oral magnesium has not been evaluated for this purpose.
• Allergic rhinitis (hay fever). Although there has been interest in using oral magnesium for allergic rhinitis, there is insufficient reliable information about the clinical effects of magnesium for this purpose.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral magnesium is beneficial in children with ADHD. Details: Children with ADHD seem to have lower magnesium levels in their blood and hair (9969,100262,100263). A small clinical study in children aged 7-12 years with ADHD and magnesium deficiency shows that taking magnesium aspartate and lactate 6 mg/kg daily for 6 months might improve hyperactivity and magnesium levels when compared with control (1189). Another small clinical study in children with ADHD but without magnesium deficiency shows that taking magnesium 6 mg/kg daily along with vitamin D 50,000 IU weekly for 8 weeks may modestly improve emotional problems, but not inattention or hyperactivity, as measured on the strength and difficulties questionnaire (SDQ), when compared with placebo (105914).
• Back pain. It is unclear if oral or intravenous magnesium is beneficial for acute or chronic back pain in adults. Details: One open-label clinical study in adults with acute low-back pain shows that taking magnesium 365 mg once daily in addition to taking etodolac 400 mg twice daily for 10 days does not further reduce pain when compared with taking etodolac alone (105913). Magnesium has also been tried for chronic back pain. A small clinical study in patients with chronic low-back pain shows that receiving magnesium sulfate 1 gram in 250 mL normal saline intravenously every 4 hours for 2 weeks, followed by magnesium gluconate 100 mg and magnesium oxide 400 mg by mouth daily for 4 weeks, reduces pain severity when compared with placebo (90035). It is unclear if oral magnesium used alone is beneficial.
• Bariatric surgery complications. It is unclear if oral magnesium supplementation improves metabolic parameters after bariatric surgery. Details: A retrospective study of over 3000 post-bariatric surgery patients suggests that those who take oral magnesium supplements providing 100-450 mg elemental magnesium daily may have improved metabolic parameters over 4 years of follow-up. When patients taking magnesium supplements were compared with those not taking supplements, 11% and 18% had type 2 diabetes, respectively, 30% and 42% had hypertension, respectively, and 16% and 23% had elevated low-density lipoprotein (LDL) cholesterol levels, respectively. For patients with hypomagnesemia at baseline, supplementation seemed to result in greater benefits (108968).
• Bipolar disorder. Taking magnesium orally might improve manic symptoms in some people with bipolar disorder; however, it is unclear how it compares to current standard of care. Details: One preliminary clinical study shows that magnesium 40 mEq daily (Magnesiocard) for 32 weeks has similar effects to lithium in up to 50% of patients treated for rapid cycling bipolar affective disorder (61022). Another preliminary clinical study shows that magnesium oxide 375 mg orally daily plus verapamil 80 mg taken four times daily reduces manic symptoms more effectively than verapamil alone in patients with mania (60742).
• Cancer-related neuropathic pain. It is unclear if intravenous magnesium is beneficial for this condition. Details: Single 500 mg to 1 gram doses of magnesium sulfate seem to relieve neuropathic pain for up to four hours when compared to baseline (6846). The validity of this finding is limited by the lack of a comparator group.
• Cardiac arrest. Intravenous magnesium does not seem to be helpful in cardiac arrest; however, the risk of sudden cardiac death seems to be inversely correlated to higher plasma magnesium levels or dietary intake. It is unclear if magnesium supplementation is associated with similar risk reduction. Details: Administering magnesium intravenously doesn't seem to improve successful resuscitation in people with cardiac arrest (1190). However, higher plasma magnesium levels and higher dietary magnesium intake might reduce the risk of sudden cardiac death, possibly by protecting against fatal ventricular arrhythmias. In the Nurses' Health Study, the risk of sudden cardiac death was 77% lower in females with the highest quartile of plasma magnesium levels when compared with the lowest quartile. Also, the risk was 37% lower in females with the highest quartile of dietary magnesium intake when compared with the lowest quartile (17132).
• Cardiovascular disease (CVD). Evidence regarding the effect of dietary magnesium on CVD risk is conflicting. Details: Epidemiological research in some populations shows that increased dietary magnesium intake is associated with decreased mortality due to strokes, coronary heart disease, ischemic heart disease, and heart failure, but other epidemiological research does not show any effect on these risks (89391,90003,90009,90030,90036,103735). Reasons for the discrepancies may be related to serum levels of magnesium at baseline, risk of cardiovascular disease at baseline, use of concomitant medications such as diuretics, or the presence of concomitant conditions such as kidney dysfunction. A population analysis conducted in Denmark has found that magnesium intake from drinking water may be associated with cardiovascular mortality. The overall risk of cardiovascular death and death due to stroke was reduced by 4% in the lowest 3 quintiles of intake when compared with the highest quintile. However, the risk of death due to acute myocardial infarction was increased by 22% in the lowest quintile when compared with the highest (108726). The relevance of these results is unclear, given that the main dietary source of magnesium is food rather than drinking water.
• Chronic fatigue syndrome (CFS). Limited evidence suggests that magnesium may help improve CFS symptoms, but this is controversial. Details: In people with low red blood cell magnesium, there is some evidence that intramuscular injections of 1 gram magnesium sulfate given once weekly for 6 weeks might improve CFS symptoms (7556). However, there is additional evidence that most patients with CFS have normal magnesium stores, and measurement of red cell magnesium is a poor indicator of total magnesium stores (7557,8084,8085,8086,8087).
• Chemotherapy-induced leukopenia. It is unclear if oral magnesium is beneficial in pediatric patients at risk for cisplatin-induced febrile neutropenia. Details: A small clinical study in children with solid tumors aged 9 years and older shows that taking magnesium 250 mg daily while receiving cisplatin-based chemotherapy reduces febrile neutropenia by 47% and septic shock by 57% when compared with not receiving magnesium. Results from this study suggest that four pediatric patients need to take oral magnesium to avoid one case of febrile neutropenia (104394).
• Chemotherapy-induced nephrotoxicity. It is unclear if intravenous magnesium is beneficial for chemotherapy-induced nephrotoxicity. Details: A meta-analysis of several lower quality clinical studies in adults in Japan with cancer receiving cisplatin shows that pretreatment with intravenous magnesium sulfate 5 to 20 mEq reduces the odds of chemotherapy-induced nephrotoxicity in a dose-dependent manner when compared to standard hydration therapy (115726). The validity of these findings is limited by heterogenous methods between clinical trials, including types of cancer, definitions of nephrotoxicity, and use of other nephroprotective therapies.
• Chronic obstructive pulmonary disease (COPD). Intravenous, but not nebulized, magnesium may be helpful in acute exacerbations of COPD. Details: Administering magnesium sulfate intravenously, 1.2-2.5 grams over 20 minutes, might be helpful for treating acute exacerbations of COPD (1208,6844,103733). Also, giving magnesium sulfate 2 grams intravenously seems to improve exercise capacity when compared with placebo (89384). A meta-analysis of studies using intravenous magnesium sulfate for COPD exacerbations shows that it reduces hospital admission and mean length of stay and improves dyspnea scores when compared with placebo. Based on the relative risk identified in the included studies, seven patients would need to receive intravenous magnesium to prevent one hospitalization. However, intravenous magnesium sulfate does not change the need for non-invasive ventilation and the available research did not evaluate intensive care unit (ICU) admission (108967). Nebulized magnesium has also been evaluated. In patients experiencing a COPD exacerbation, clinical research shows that administering nebulized magnesium sulfate with albuterol three times at 30-minute intervals does not improve pulmonary function as measured by the forced expiratory volume in 1 second (FEV1) when compared with placebo (89393). Also, a meta-analysis of a small number of low-quality studies shows that nebulized magnesium does not reduce hospital admission or the need for ventilatory support, although it might modestly improve dyspnea scores and reduce ICU admissions, when compared with placebo (108967).
• Cluster headache. It is unclear if a single intravenous dose of magnesium sulfate is beneficial for cluster headaches. Details: Administering magnesium sulfate intravenously, 1 gram over 5 minutes, seems to improve cluster headaches when compared with baseline(1184). The validity of this finding is limited by the lack of a comparator group.
• Cognitive impairment. It is unclear if oral magnesium is beneficial for cognitive impairment. Details: A large observational study in adults with end-stage renal disease on hemodialysis suggests that serum magnesium levels of 20.2-22.3 mg/dL are associated with the lowest odds of mild cognitive impairment, while serum magnesium levels below and above that range of values are associated with increased odds of mild cognitive impairment (111695).
• Coronary heart disease (CHD). It is unclear if magnesium supplementation is beneficial for CHD. Details: Clinical research shows that magnesium oxide 800-1200 mg daily for 3 months reduces platelet-dependent thrombosis by 35% when compared with placebo in patients with CHD (60759). It is unclear if this effect improves clinical outcomes. The effect of magnesium supplementation on coronary artery calcium has also been studied. A meta-analysis of 3 clinical studies in 196 patients with chronic kidney disease (CKD) shows that taking magnesium or increasing the concentration of magnesium in dialysate does not improve coronary artery calcification (CAC) scores when compared with standard therapy. However, magnesium reduced carotid intima-media thickness (111179). Similarly, a large clinical study in patients with CKD shows that taking slow-release magnesium hydroxide (Mablet, Denmark) 360 mg twice daily for 12 months does not slow the progression of CAC scores when compared with placebo (111178). This study may not have been adequately powered to detect a difference between groups.
• Coronavirus disease 2019 (COVID-19). It is unclear if oral magnesium is beneficial for COVID-19. Details: A small clinical study in patients hospitalized with moderate COVID-19 shows that taking magnesium 300 mg daily for the duration of hospitalization reduces the number of patients requiring oxygen therapy but not the duration of hospital stay when compared with placebo (114680).
• Depression. It is unclear if magnesium is beneficial for the treatment or prevention of depression in adults. Details: Some population research shows that dietary intake of elemental magnesium between 76-360 mg daily is associated with a reduced risk of depression, but there was no association with greater amounts of magnesium, and other population research shows no association at any intake level (96480,98289). For treatment of mild to moderate depression, one preliminary clinical study shows that taking magnesium chloride 2 grams orally daily for 6 weeks reduces depression scores by 56% and anxiety scores by about 52% when compared to baseline (96477). The validity of these findings is limited by the lack of a comparator group. However, a small clinical study in adults with recurrent depression shows that taking magnesium aspartate 120 mg daily for 8 weeks, along with fluoxetine, does not improve depression scores when compared with patients taking fluoxetine and placebo (111185). Similarly, a very small crossover clinical study in adults with mild or moderate treatment-resistant depression shows that administering a single dose of IV magnesium sulfate 4 grams does not improve depression scores when compared with an infusion of 5% dextrose (96481). However, scores were evaluated 24 hours post-infusion which may be too soon to detect improvement. Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that elemental magnesium in doses of 100-400 mg is not recommended for adjunctive or monotherapy use in patients with depression (110318).
• Diabetic foot ulcers. Oral magnesium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with grade 3 diabetic foot ulcers shows that taking magnesium oxide 250 mg plus vitamin E 400 IU daily for 12 weeks modestly reduces ulcer size when compared with placebo (101436). It is unclear if this effect is due to magnesium, vitamin E, or the combination.
• Exercise-induced muscle soreness. It is unclear if oral magnesium reduces muscle soreness in adults after resistance training. Details: A very small study in healthy adults, ages 19-23, shows that taking magnesium glycinate 350 mg daily for 10 days seems to reduce muscle soreness after bench press exercise when compared with placebo (104399).
• Fetal and premature infant mortality. It is unclear if antenatal intravenous (IV) magnesium sulfate administration reduces the risk of fetal and premature infant mortality. Details: Two meta-analyses of up to 7 clinical studies in patients at risk of preterm birth shows that antenatal IV magnesium sulfate administration does not reduce the risk of fetal or neonatal death when compared with placebo (114675,114681).
• Fibromyalgia. It is unclear if oral magnesium is beneficial for this condition. Details: A small clinical study shows that taking magnesium chloride orally 100 mg once daily for one month reduces mild to moderate, but not severe, stress associated with fibromyalgia when compared with placebo. It also reduces pain levels, but not to a clinically significant extent, and it does not affect sleep, fatigue, or quality of life (108964). Another small clinical study shows that taking magnesium citrate 300 mg daily for 8 weeks improves some symptoms of fibromyalgia, such as number of tender points and depression, when compared to baseline (89385). The validity of this finding is limited by the lack of a comparator group. A small clinical study shows that taking a combination of magnesium hydroxide and malic acid (Super Malic tablets) orally decreases fibromyalgia-related pain and tenderness in some patients when compared with placebo (3262). It is unclear if this effect is due to magnesium, malic acid, or the combination.
• Fractures. Population research suggests that higher intakes of magnesium may reduce fracture risk. Details: Observational research has found that higher dietary and supplemental magnesium intake is associated with a 34% lower odds of fracture when compared with lower magnesium intake (101395).
• Gastric cancer. Population research suggests that higher intakes of magnesium may reduce gastric cancer risk. Details: Observational research has found that higher dietary and supplemental magnesium intake is not associated with a reduced risk for gastric cancer when compared with lower intake (103730).
• Hearing loss. Oral magnesium may prevent and improve hearing loss due to environmental factors or loud noises. Details: Clinical research in healthy military recruits shows that taking magnesium aspartate 167 mg daily for 2 months prevents hearing loss from exposure to loud noises during basic military training when compared with placebo (1205). Also, in patients with acute-onset hearing loss that was not caused by environmental factors, taking magnesium aspartate 167 mg daily for 8 weeks seems to improve hearing loss when compared with placebo (60813).
• Hypertension. Oral magnesium supplementation may modestly reduce blood pressure, although these changes are not likely to be considered clinically significant. Details: Most research shows that taking oral magnesium supplements in daily doses that are at least as high as the Recommended Dietary Allowance (RDA) for adults and up to 1000 mg daily can lower diastolic blood pressure by about 2 mmHg in adults with or without hypertension (1192,1199,9465,15165,18111,96482). Significantly lower doses do not seem to have this effect (1180,1195,1197,8098). The effect of magnesium on systolic blood pressure is conflicting. Two meta-analyses shows that taking magnesium 212-970 mg daily does not lower systolic blood pressure in patients with or without hypertension (15165,115728). However, additional meta-analyses show that taking magnesium 120-970 mg daily can lower systolic blood pressure in a dose-dependent manner by about 2-4 mmHg in patients with or without hypertension (18111,96482). The reasons for these discrepant findings are unclear but may be due to heterogenous methods, including dose and duration among clinical studies. In 2022, the US Food and Drug Administration (FDA) approved a qualified health claim stating that inconsistent and inconclusive evidence suggests that diets with adequate magnesium may reduce the risk of high blood pressure. Products bearing this claim must provide at least 84 mg of magnesium daily, but no more than 350 mg daily (107451).
• Hypokalemia. It is unclear if intravenous or oral magnesium is beneficial for hypokalemia in patients with normal magnesium levels. Details: A preliminary retrospective observational study in patients with hypokalemia and unknown serum magnesium levels has found that administering oral or intravenous magnesium is not associated with improved time to normalization of serum potassium levels when compared with no magnesium treatment (110049). However, hypokalemia with concurrent hypomagnesemia can impede potassium repletion and exacerbate hypokalemia-induced rhythm disturbances. Standard of care in patients with hypokalemia and known hypomagnesemia includes prompt treatment with magnesium (110063).
• Impaired glucose tolerance (prediabetes). It is unclear if oral magnesium is beneficial for prediabetes. Details: Preliminary clinical research in patients with prediabetes shows that taking magnesium oxide 250 mg orally daily for 12 weeks does not improve fasting blood glucose levels, insulin resistance, or glycated hemoglobin (HbA1C) levels when compared with placebo. Taking magnesium also did not affect blood pressure, body weight, triglyceride levels, or low-density lipoprotein cholesterol levels; however, it did modestly improve high-density lipoprotein cholesterol levels (110053).
• Insomnia. Oral magnesium may modestly improve sleep complaints in adults, but evidence is conflicting. Details: A meta-analysis of two small clinical studies in healthy older adults with or without insomnia suggests that taking magnesium reduces the time to fall asleep by an average of 17 minutes when compared with placebo (105917). However, it does not increase the time spent asleep. Also, these findings are limited by imprecision and a high risk of bias. Studies included in the analysis used elemental magnesium 500-729 mg daily (as magnesium oxide) for up to 8 weeks (102458,105917). Another small clinical study in patients with poor sleep quality and low magnesium status shows that taking elemental magnesium 320 mg (as magnesium citrate) in divided doses daily for 7 weeks does not improve sleep quality, as measured by the Pittsburgh Sleep Quality Index (PSQI), when compared with a sodium citrate placebo (102456). Magnesium has also been evaluated in combination with other ingredients. A very small crossover clinical study in patients aged 18-40 years without a sleep disorder shows that taking a combination of magnesium 300 mg, L-tryptophan 1000 mg, glycine 3000 mg, tart cherry 220 mg, and theanine 200 mg for 3 days reduces the time to fall asleep by about 24 minutes, increases total time asleep by about 22 minutes, and improves sleep efficiency, but does not improve the total time in bed or wakefulness after falling asleep when compared with cellulose placebo (111184). Another small crossover clinical study in adults with sleep disturbances shows that taking a combination of magnesium 200 mg and melatonin nightly for 4 weeks improves sleep quality, as measured by the PSQI, reduces the length of time it takes to fall asleep by about 17 minutes, and improves some other measures of sleep, such as sleep efficiency and number of awakenings, when compared with placebo. However, despite these improvements, overall sleep quality was still categorized as poor after the intervention (113670). It is unclear if these effects are due to magnesium, other ingredients, or the combination.
• Intraventricular hemorrhage. It is unclear if antenatal intravenous (IV) magnesium sulfate can reduce the risk for intraventricular hemorrhage in neonates. Details: A meta-analysis of clinical research in premature infants shows that if the mother received antenatal intravenous magnesium sulfate, the infant had a non-significant trend toward a reduced risk of intraventricular hemorrhage when compared with infants whose mothers received placebo (103727). This analysis may have been insufficiently powered to detect a difference between groups. Another meta-analysis of up to 6 clinical studies, some of which are included in the previously referenced meta-analysis, in patients at risk of preterm birth shows that maternal antenatal (IV) magnesium sulfate administration does not reduce the risk of intraventricular hemorrhage, but does reduce the risk of severe intraventricular hemorrhage by about 24% when compared with placebo (114681).
• Kidney stones (nephrolithiasis). Taking magnesium orally may prevent the recurrence of kidney stones, although evidence is conflicting. Details: Prophylactic treatment with magnesium hydroxide, 200 mg twice daily for one year, followed by 500 mg daily for another year, might decrease the recurrence rate of calcium stone formation (2007). However, magnesium oxide does not seem to benefit patients considered to be recurrent calcium stone formers when compared with placebo, no treatment, or chlorthalidone (8097,38501,61199). Magnesium oxide 300 mg in combination with vitamin B6 10 mg daily seems to decrease urinary oxalate levels in people with hyperoxaluria who have previously had kidney stones (1201), but it is unclear if this effect translates into a reduced incidence of kidney stones.
• Liver cancer. Increased dietary magnesium intake is linked with a lower risk of liver cancer. Details: Observational research in retired older Americans has found that higher dietary magnesium intake is associated with a 35% lower risk of liver cancer when compared with lower intake. This association was especially strong in persons who were moderate or heavy alcohol users (105080).
• Lung cancer. Supplemental or dietary magnesium intake does not seem to reduce the risk of lung cancer. Details: A large epidemiological cancer screening trial with a mean follow-up of over 12 years suggests there is no association between dietary or supplemental magnesium intake and the risk of lung cancer. However, dietary magnesium seems to play an important yet unclear role in lung cancer prevention when taken as part of the diet with alpha-carotene, vitamin C, vitamin E, lycopene, selenium, lutein, and zeaxanthin (112096).
• Migraine headache. Oral magnesium may help prevent migraine in some adults and children. Also, intravenous magnesium may help treat migraine in adults, but evidence is conflicting. Details: A meta-analysis of 4 low-quality clinical studies, in adults with migraine shows that magnesium 122-600 mg daily for 4-16 weeks modestly reduces migraine frequency and severity when compared with placebo(115730). However, clinical significance is unclear, and the validity of these findings is limited by heterogeneous methods between clinical trials, including type of magnesium formulation and dose, patient population, and duration. In contrast, one small clinical study shows that taking magnesium does not reduce migraine frequency and severity by at least 50% in adults when compared with placebo (10661). Limited evidence suggests that adding oral magnesium to conventional treatment may also be beneficial. A clinical study in adults with migraine living in Iran shows that taking magnesium oxide 250 mg twice daily in addition to sodium valproate 200 mg twice daily for 12 weeks modestly reduces severity and duration of migraine, but not migraine frequency, when compared with taking sodium valproate alone (105915). It is unclear if these improvements would be considered clinically significant. For treatment of migraine, some adults with normal magnesium levels respond to intravenous (IV) magnesium sulfate 1 gram over 5 minutes, but most patients who benefit have low magnesium levels at baseline (1185,6844). Effects of IV magnesium in patients with unknown magnesium levels are conflicting. Some preliminary clinical research shows that magnesium 1-2 grams IV alleviates acute migraine for up to 2 hours, but other research has found no benefit (89388,97493,98285). In children, treatment with magnesium oxide orally 15 mg/kg daily in 3 divided doses for up to 16 weeks reduces the frequency and severity of migraine headaches when compared with placebo (10663). However, adding magnesium sulfate 400 mg orally daily to ibuprofen or acetaminophen does not further reduce migraine severity in children (89396).
• Miscarriage. Oral magnesium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in pregnant adults with threatened miscarriage between the 6th and 13th week of gestation shows that taking a specific combination product (DAV HA, Lo.Li pharma s.r.l) containing magnesium 450 mg, alpha-lipoic acid, hyaluronic acidvitamin B6, and vitamin D daily in combination with conventional treatment of vaginal progesterone over 2 weeks of observation results in a faster resorption of the subchorionic hematoma and faster decrease of patient-reported vaginal bleeding, abdominal pain, and uterine contractions when compared with vaginal progesterone alone (113893). It is unclear if these effects are due to magnesium, other ingredients, or the combination. Additionally, the validity of these findings is limited by the lack of a placebo in the control group.
• Myocardial infarction (MI). Research on the effects of intravenous or oral magnesium after myocardial infarction are conflicting. Details: Administering magnesium intravenously doesn't seem to reduce mortality after an acute MI (8999,13357,13358,13359,13360,19990,60872,61082), although there is some conflicting evidence from a meta-analysis of clinical research that shows that intravenous magnesium sulfate may reduce short-term mortality by 55% when compared with placebo (60795,60895). Clinical research with oral magnesium supplementation has found no benefit (1198,6844).
• Neonatal encephalopathy. Intravenous magnesium may improve short-term outcomes in neonates with encephalopathy. Details: A meta-analysis of clinical research shows that intravenous magnesium may improve short term outcomes of neonatal encephalopathy (hypoxic ischemic encephalopathy, HIE). However, long term outcomes are not affected (90025).
• Nocturnal leg cramps. It is unclear if oral magnesium is helpful for nocturnal leg cramps. Details: Some clinical research in adults with nocturnal leg cramps shows that taking magnesium oxide 865 mg daily at bedtime for 4 weeks does not reduce the frequency of leg cramping episodes when compared with placebo (96478). However, four weeks may be too short a time to see a benefit. In other clinical research, taking oral magnesium oxide monohydrate 226mg daily at bedtime for 60 days reduces the frequency of leg cramps when compared with placebo. This reduction was not seen after 30 days. Magnesium also reduced cramp duration and improved sleep quality, but did not affect pain scores, at 60 days when compared with placebo (106919).
• Nonalcoholic fatty liver disease (NAFLD). Oral magnesium hydroxide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with NAFLD shows that taking magnesium hydroxide 150 mg and L-carnitine 2000 mg daily for 16 weeks does not improve liver stiffness scores when compared with baseline or controls who took placebo for 8 weeks followed by this magnesium and L- carnitine combination for 8 weeks. Taking magnesium and L-carnitine also did not improve levels of aspartate aminotransferase (AST) or alanine transaminase (ALT) when compared to baseline (111177).
• Obesity. Evidence on the use of magnesium for weight loss in obese patients is conflicting; any benefit is likely small at best. Details: A meta-analysis of 7 clinical studies in obese patients shows that taking magnesium reduces body mass index (BMI) by 0.3 when compared with control (103723). Another meta-analysis of 7 studies in obese patients shows that while magnesium supplementation does not reduce weight, it reduces waist circumference by 2 cm when compared with placebo (103729). Interestingly, subgroup analyses did not find that the dose of magnesium or baseline magnesium levels impacted effectiveness. One subgroup analysis found that magnesium supplementation lasting 12 weeks or less seemed to be more beneficial for obesity than supplementation lasting longer than 12 weeks (103723).
• Overall mortality. It is unclear if oral or IV magnesium reduces the risk of overall mortality. Details: A meta-analysis of heterogeneous observational studies has found that increased dietary magnesium intake, but not supplemental magnesium intake, is associated with a modestly reduced risk of overall mortality (105073). A meta-analysis of 3 small, low-quality clinical studies in ICU patients shows that administering IV magnesium 24-30 mmol or as a target-directed dose for 3 days reduces overall mortality when compared with patients who did not receive magnesium (111290). However, some studies included patients with hypomagnesemia; it is unclear if effects would be similar for patients with normal levels of magnesium.
• Osteoarthritis. Population research has not found a link between magnesium intake and osteoarthritis risk. Details: Observational research has found that dietary and supplemental magnesium intake is not associated with the risk of developing osteoarthritis (101395).
• Pain (acute). It is unclear if locally injected or intravenous magnesium is helpful for acute pain. Details: Preliminary clinical research in patients with renal colic shows that intravenous (IV) magnesium sulfate, 50 mg/kg infused over 20 minutes, is as effective as IV morphine sulfate 0.1 mg/kg for controlling acute renal pain at 20 minutes after the dose (107367). Magnesium has also been evaluated in a dental procedure. A single-center clinical study in India in adults with irreversible pulpitis requiring a root canal shows that a local injection of 0.2 mL of 10% magnesium sulfate with lidocaine and epinephrine reduces perioperative pain when compared to lidocaine with epinephrine alone (115729).
• Pain (chronic). Population research suggests that higher intakes of magnesium may modestly reduce the risk for chronic pain. Details: A cross-sectional observational study has found that increased magnesium intake is associated with a 7% to 8% reduced risk for chronic pain. The association was found to be stronger in females than in males (103732).
• Parturition. It is unclear if topical magnesium is beneficial for labor duration. Details: A single-center clinical study in Iranian adults shows that applying 10 mL of a 50% magnesium sulfate solution directly to the cervix during the active phase of labor reduces the time to vaginal delivery by approximately 1.5 hours and improves the childbirth experience, as reported by patients, when compared with placebo. However, clinical significance is unclear (115727).
• Perioperative anxiety. It is unclear if oral magnesium is beneficial for perioperative anxiety. Details: Preliminary clinical research in adults undergoing open heart surgery shows that taking magnesium oxide 250 mg orally twice daily during hospitalization moderately improves anxiety and depression scores when compared with no magnesium therapy. Magnesium therapy was held for the 2 days immediately following surgery (110054).
• Physical performance. Oral magnesium may modestly improve physical performance in otherwise healthy, elderly females. Details: Clinical research in otherwise healthy elderly females shows that taking a magnesium oxide supplement (Easymag, Sanofi-Aventis) 900 mg daily for 12 weeks modestly improves walking speed and chair stand speed in elderly females when compared with no treatment (90026).
• Polycystic ovary syndrome (PCOS). It is unclear if oral magnesium is beneficial for improving metabolic indices in patients with PCOS. Details: Two small clinical studies in patients with PCOS show that taking magnesium oxide orally, 250 mg daily for 8 weeks, does not affect insulin resistance, beta-cell function, lipid levels, or insulin sensitivity when compared with placebo (103725,105887). Other clinical research in patients with PCOS shows that taking magnesium oxide orally, 250 mg daily for 10 weeks, improves subjective measures of quality of life, fatigue, and emotional functioning, but not objective measures such as alopecia, abnormal uterine bleeding, or acne, when compared with placebo (108965). A clinical study using a combination of magnesium 250 mg with vitamin E 400 mg daily for 12 weeks shows a modest reduction in insulin resistance, insulin levels, and triglyceride levels, but not other lipid levels, when compared with placebo (100264). It is unclear if these beneficial effects are due to magnesium, vitamin E, or the combination.
• Postoperative nausea and vomiting (PONV). It is unclear if intravenous (IV) magnesium is beneficial for PONV due to mixed results from clinical research. Details: A meta-analysis of 5 clinical studies in adults undergoing surgery with general anesthesia shows that administering IV magnesium sulfate intraoperatively reduces PONV (114676). However, a meta-analysis of 20 clinical studies in adults undergoing surgery with general anesthesia shows that administering IV magnesium perioperatively does not reduce the incidence of PONV (114678). A moderate-sized clinical study conducted in China in older adults undergoing total knee arthroplasty shows that administering intravenous magnesium sulfate 40 mg/kg prior to anesthesia induction then 15 mg/kg during surgery reduces the incidence of postoperative vomiting but not postoperative nausea when compared with control (113677). The reasons for these discrepant findings are unclear but may be explained by differences in magnesium regimens, anesthesia protocols, and surgical populations studied.
• Postoperative recovery. It is unclear if intravenous (IV) magnesium is beneficial for postoperative recovery. Details: A moderate-sized clinical study conducted in China in older adults undergoing total knee arthroplasty shows that administering IV magnesium sulfate 40 mg/kg prior to anesthesia induction then 15 mg/kg during surgery does not reduce extubation time, time spent in the post-anesthesia care unit (PACU), or duration of hospital stay when compared with control (113677). Additionally, a meta-analysis of 3 different clinical studies in adults undergoing surgery with general anesthesia shows that administering IV magnesium intraoperatively does not reduce extubation time (114676).
• Postoperative sleep disturbance. It is unclear if oral magnesium is beneficial for postoperative sleep disturbances. Details: Preliminary clinical research in adults undergoing open heart surgery shows that taking magnesium oxide 250 mg orally twice daily during hospitalization moderately improves sleep scores when compared with no magnesium therapy. Magnesium therapy was held for the 2 days immediately following surgery (110054).
• Postoperative sore throat. It is unclear if topical magnesium sulfate is beneficial for reducing sore throat pain after endotracheal intubation. Details: Preliminary clinical research in patients undergoing endotracheal intubation for surgery shows that using a gargle containing magnesium sulfate 20% with lidocaine, 20 minutes before anesthesia induction, is less effective for reducing sore throat pain than a gargle containing dexmedetomidine and lidocaine (112779). The study did not include a comparison to lidocaine alone.
• Pregnancy-related leg cramps. It is unclear if oral magnesium reduces leg cramps during pregnancy; evidence is conflicting. Details: One small clinical study in patients with pregnancy-related leg cramps shows that taking magnesium bisglycinate chelate 300 mg daily for 4 weeks reduces the frequency and intensity of leg cramps when compared with placebo (99318). A smaller clinical study in this population shows that taking a specific mixture of magnesium lactate and citrate (Nycoplus Magnesium) providing elemental magnesium 120 mg in the morning and 240 mg in the evening for 3 weeks reduces the frequency of cramps when compared with placebo (1194). However, not all research agrees. One small clinical study using this same supplement and dose for 2 weeks found no benefit when compared with placebo (17463). It is possible that a 2-week duration of treatment is too short to be beneficial. Finally, a meta-analysis of these studies and one other more recent clinical study shows that taking magnesium does not reduce the frequency or improve the resolution of pregnancy-related leg cramps when compared with placebo (105916). This analysis may not have been adequately powered to detect a difference between treatment groups.
• Pre-procedural sedation. It is unclear if intravenous magnesium is beneficial when administered in addition to other medications used for sedation during surgery. Details: A moderate-sized study of adults aged 65-79 years old undergoing endoscopic retrograde cholangiopancreatography (ERCP) shows that administering a single intravenous bolus of magnesium sulfate 40 mg/kg prior to the procedure reduces intraoperative propofol requirements by about 21% and reduces some peri-procedural adverse events including the incidence of respiratory depression and involuntary movement when compared with control. However, there were no differences in recovery time, hemodynamic parameters, or the incidence of hypotension, bradycardia, perioperative nausea or vomiting, lethargy, or arrythmias (111694). Another moderate-sized study in older adults undergoing total knee arthroplasty shows that administering intravenous magnesium sulfate 40 mg/kg prior to anesthesia induction then 15 mg/kg during surgery does not reduce the need for medications used for anesthesia induction, intraoperative maintenance propofol requirements, or recovery time when compared with control. However, magnesium sulfate does seem to reduce the amount of remifentanil required for intraoperative anesthesia maintenance and increase norepinephrine requirements when compared with control (113677).
• Preterm labor. The use of magnesium sulfate to inhibit uterine contractions in preterm labor (tocolysis) is controversial. However, its use for the purpose of fetal neuroprotection for up to 48 hours is supported by the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine. Details: Magnesium is given intravenously (IV) during preterm labor in an effort to improve fetal neurological outcomes, such as to reduce the risk of cerebral palsy and motor dysfunction in the infant (60915,60927,60931,61001,97485,103734,103754,114681). The typical dosage of magnesium sulfate is 4 grams infused IV over 10-30 minutes, followed by a maintenance infusion of 1-4 grams/hour for 48 hours or until birth. Use beyond 5-7 days has been associated with hypocalcemia and bone abnormalities in the fetus (15,12590,12594). Some meta-analyses of clinical research suggest that magnesium sulfate is more effective at delaying delivery by 48 hours when compared with oxytocin receptor blockers, nitrates, beta-mimetics, and/or placebo (20263,61021). However, an additional meta-analysis of several clinical studies shows that magnesium sulfate 4 or 6 grams IV is not more effective at delaying preterm labor by 48 hours when compared with nifedipine (115639). The reason for these discrepant findings are unclear, but may be related to the heterogenous methods between clinical trials, including dose and duration.
• Pseudoxanthoma elasticum (PXE). It is unclear if oral magnesium is beneficial for PXE. Details: Preliminary clinical research in patients with PXE shows that taking magnesium oxide 800 mg (500 mg of elemental magnesium) twice daily for one year tends to reduce calcification of elastic skin fibers when compared with placebo, but the effect is not statistically significant (101393). This study was limited by small size and insufficient power to detect smaller effects.
• Restless legs syndrome (RLS). It is unclear if oral magnesium is beneficial for RLS. Details: Some observational research has found that hypomagnesemia is associated with RLS; however, not all research agrees (8096,9472). Preliminary clinical research in adults with RLS who are beginning treatment with pramipexole shows that also taking magnesium oxide 250 mg orally daily for 2 months moderately improves RLS scores and sleep quality scores when compared with pramipexole and placebo (110052). Other low-quality clinical research in adults with RLS or periodic limb movement during sleep shows that taking magnesium 12.4 mmol orally in the evening for 4-6 weeks decreases movement and increases sleep when compared with baseline (9466). The validity of this finding is limited by the lack of a comparator group.
• Sarcopenia. It is unclear if oral magnesium is beneficial for the prevention or treatment of sarcopenia. Details: Population research in older adults has found that lower dietary intake of magnesium is associated with sarcopenia. However, the effect of magnesium supplementation on sarcopenia prevention or treatment has not been evaluated (110055). Magnesium has been evaluated in combination with other ingredients for treatment of sarcopenia. A small clinical study in elderly individuals with sarcopenia undergoing a diet and exercise program shows that taking a combination supplement containing magnesium 300 mg, carnosine, hydroxymethylbutyrate, lactoferrin, and sodium butyrate daily for 4 months increases muscle mass, as measured by the skeletal muscle index, and improves measures of muscle function, including handgrip muscle strength, chair test, and walking speed, when compared with placebo (114682). It is unclear if these effects are due to magnesium, other ingredients, or the combination.
• Sepsis. It is unclear if intravenous magnesium is beneficial for sepsis. Details: A very large observational study in patients with sepsis and hypomagnesaemia or normomagnesemia in the intensive care unit (ICU) suggests that administering intravenous magnesium sulfate 2 or 4 grams within 24 hours of admission reduces 28-day all-cause mortality from 25% in patients who did not use magnesium sulfate to 20% in those who were administered magnesium sulfate, regardless of baseline serum magnesium level and other baseline characteristics. Administration of intravenous magnesium sulfate in this population may also reduce ICU mortality by 4%, in-hospital mortality by 3%, and the use of renal replacement therapy by 3% but also seems to increase the length of ICU and hospital stay when compared with patients who did not use magnesium sulfate (113676). The validity of these results is limited by the observational nature of the study.
• Sleep deprivation. Oral magnesium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in sleep-deprived recreational athletes shows that taking a combination of magnesium 1350 mg, zinc 90 mg, and vitamin B6 31.5 mg for 3 nights at bedtime does not change sleep quality, subjective sleepiness, mood, or fatigue the next day when compared with placebo (113655).
• Stroke. Increased dietary magnesium may decrease stroke risk, and using a magnesium-containing salt substitute may improve neurological performance post-stroke. However, intravenous magnesium has not demonstrated benefit. Details: Most population research has found that increased dietary intake of magnesium is associated with decreased stroke risk and decreased mortality from stroke (9001,9002,90013,90030,90036,92107,103736). In patients who have had a stroke, a preliminary clinical study shows that using a salt substitute providing the Dietary Reference Intake (DRI) of magnesium and potassium for 6 months improves neurological performance when compared with using regular salt (97491). However, intravenous (IV) magnesium does not seem to be beneficial in patients who have had a stroke. Large prospective clinical trials show that IV magnesium given within 12 hours of acute stroke does not reduce mortality or disability in most patients when compared with placebo. However, one subgroup analysis suggested that IV magnesium might benefit patients with lacunar (non-cortical) stroke (13361,90021). IV magnesium also doesn't seem to reduce cardiovascular complications after acute stroke. A secondary analysis of a clinical trial in patients after ischemic and hemorrhagic stroke shows that giving IV magnesium does not reduce serious cardiac adverse events when compared with placebo (104393). Another secondary analysis of this trial shows that giving IV magnesium prior to arrival at the hospital and within 2 hours of a hemorrhagic stroke does not reduce hematoma volume on hospital arrival, hematoma expansion during hospital admission, or functional outcomes at 3 months (108733).
• Subarachnoid hemorrhage. Intravenous magnesium sulfate may reduce the risk of adverse outcomes in people with subarachnoid hemorrhage, but evidence is conflicting. Details: There is mixed evidence regarding the effect of magnesium sulfate in managing aneurysmal subarachnoid hemorrhage. One meta-analysis of clinical research shows that intravenous magnesium sulfate 64-144 mmol/day for 10-18 days reduces the risk of poor outcomes following aneurysmal subarachnoid hemorrhage, including death, vegetative state, or dependency, by 46% when compared with control (60932). Also, meta-analyses of clinical research show that intravenous magnesium reduces the risk of delayed cerebral ischemia by 27% when compared with placebo (60944,89398). However, these results were not confirmed in other meta-analyses (60973,90034).
• Thrombocytopenia. It is unclear if intravenous magnesium sulfate is beneficial in patients with thrombotic thrombocytopenic purpura (TTP). Details: Addition of intravenous magnesium sulfate as a 6-gram loading dose followed by 6 grams infused over 24 hours for 3 days, to standard treatment for TTP does not reduce the time to normalization of the platelet count, the incidence of TTP-related organ dysfunction, or the recurrence rate, when compared with standard treatment alone (112777). This study may have been underpowered to detect a difference.
• Urinary incontinence. Although there has been interest in using oral magnesium for urinary incontinence, there is insufficient reliable information about the clinical effects of magnesium for this purpose. More evidence is needed to rate magnesium for these uses.

(Read more about MAGNESIUM)

EFFECTIVE

• Manganese deficiency. Oral and intravenous manganese can prevent and treat manganese deficiency. Details: Taking manganese orally or intravenously is effective for preventing or treating manganese deficiency (15). However, the incidence of manganese deficiency is not well documented. Long-term home parenteral nutrition should provide no more than 55 mcg daily of manganese for adults or 1 mcg/kg daily (up to 50 mcg) of manganese for children unless clinically indicated (96416,99302). A clinical trial in children aged 8-14 months who are manganese deficient shows that taking manganese in addition to other vitamins and minerals in a 30 mL beverage six days per week for up to 14 months promotes growth when compared with placebo (19348).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). It is unclear if intranasal manganese is beneficial in patients with allergic rhinitis. Details: A small clinical study in patients with chronic allergic rhinitis shows that using an isotonic seawater nasal spray enriched with manganese (Sterimar Mn, Laboratori Baldacci) four puffs daily for 5 months, in addition to standard treatment with oral antihistamines, nasal corticosteroids, and nasal decongestants, reduces the number of acute exacerbations by about three when compared with the standard treatment alone (99416). However, the effect of the manganese in this product is unclear since nasal lavage with a plain saline nasal spray also helps in allergic rhinitis.
• Chronic obstructive pulmonary disease (COPD). Intravenous manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients being treated for exacerbation of COPD shows that intravenous supplementation with manganese 0.4 mg, selenium 100 mcg, and zinc 2 mg daily may shorten the number of days spent on mechanical ventilation when compared with placebo (61432). It is unclear if these findings are due to manganese, other ingredients, or the combination.
• Metabolic syndrome. It is unclear if oral intake of or environmental exposure to manganese decreases the risk of metabolic syndrome. Details: A meta-analysis of 12 observational studies suggests that increased dietary intake of manganese or higher levels of manganese in the serum, whole blood, or urine are not associated with a lower risk of metabolic syndrome when compared with lower manganese intake or laboratory values (112138).
• Obesity. Oral manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in overweight adults shows that taking a specific combination product (7-Keto Naturalean, Enzymatic Therapy, Inc.) containing manganese 500 mcg, 7-oxo-DHEA 100 mg, L-tyrosine 100 mg, asparagus root extract 100 mg, choline bitartrate 50 mg, inositol 50 mg, copper gluconate 500 mcg, and potassium iodide 100 mcg daily for 8 weeks reduces body weight by around 1.5 kg and body mass index (BMI) by around 0.7 kg/m² when compared with placebo (61581).
• Osteoarthritis. Oral manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Small clinical studies in patients with osteoarthritis of the knee and lower back show that taking a specific combination product (Cosamin DS, Nutramax Laboratories) containing manganese ascorbate 228-304 mg (about 31-41 mg of elemental manganese), glucosamine hydrochloride 1500-2000 mg, and chondroitin sulfate 1200-1600 mg daily for 4 months improves pain and ability to do activities of daily living when compared with baseline or placebo (4237,7169). The amount of manganese in the Cosamin DS formulation used in this study is considerably higher than the 1 mg of elemental manganese per 1500 mg of glucosamine hydrochloride in the current formulation. Since numerous studies show glucosamine with chondroitin without manganese might be effective for osteoarthritis, it is not possible to draw conclusions about the effects of manganese alone.
• Osteoporosis. Oral manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in postmenopausal patients shows that taking manganese 5 mg in combination with elemental calcium 1000 mg, zinc 15 mg, and copper 2.5 mg daily for 2 years reduces spinal bone loss when compared with placebo (1994). Another small clinical study in females with osteopenia shows that taking a specific combination product (Vitrum Osteomag, Unipharm Inc.) containing manganese 1.8 mg, calcium 600 mg, vitamin D (cholecalciferol) 200 IU, magnesium 40 mg, zinc 7.5 mg, copper 1 mg, and boron 250 mcg twice daily for one year improves bone mineral density when compared with no treatment (36840). However, since numerous studies have demonstrated the efficacy of calcium plus vitamin D for osteoporosis, it is not possible to draw conclusions about the effects of manganese alone.
• Premenstrual syndrome (PMS). Oral manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in patients with PMS shows that taking manganese 1.0 mg or 5.6 mg in combination with calcium 587 mg or 1336 mg daily for about 24 weeks improves symptoms of PMS including pain, crying, loneliness, anxiety, restlessness, irritability, mood swings, depression, and tension (2004).
• Wound healing. Topical manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Observational research has found that applying an alginate dressing containing manganese, calcium, and zinc to chronic wounds for 12 weeks is associated with improved wound healing when compared with previous treatments (61327). It is unclear if these findings are due to manganese, other ingredients, or the combination. More evidence is needed to rate manganese for these uses.

(Read more about MANGANESE)

POSSIBLY EFFECTIVE

• Neural tube birth defects. High dietary intake of methionine during pregnancy seems to reduce the risk of neural tube birth defects. Details: Population research has found that higher dietary intake of methionine during pregnancy is associated with a reduced risk of neural tube defects when compared with lower dietary intake (63117,63135).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acetaminophen poisoning. It is unclear if oral methionine is beneficial in patients with acute acetaminophen poisoning. Details: Observational research has found that taking methionine 2.5 grams every 4 hours for a total of four doses, starting within 10 hours of acetaminophen overdose, may have similar efficacy to acetylcysteine for preventing liver damage and death (2413).
• Allergic rhinitis (hay fever). Although there has been interest in using oral methionine for seasonal allergies, there is insufficient reliable information about the clinical effects of methionine for this purpose.
• Asthma. Although there has been interest in using oral methionine for asthma, there is insufficient reliable information about the clinical effects of methionine for this purpose.
• Breast cancer. It is unclear if high dietary intake of methionine reduces the risk of breast cancer. Details: A meta-analysis of observational studies suggests that higher dietary intake of methionine is associated with a 6% lower risk of breast cancer, especially for postmenopausal adults, when compared with lower intake. Increasing dietary intake of methionine by 1 gram daily may be associated with a 4% reduction in the risk of breast cancer. These results appear to be more prominent in postmenopausal adults when compared with premenopausal adults; however, this could have been by chance due to the small number of studies that assessed premenopausal adults (94093). A more recent meta-analysis, including 4 additional observational studies, suggests that there is no significant association between methionine intake and breast cancer risk. This finding is largely influenced by inclusion of the European Prospective Investigation into Cancer and nutrition (EPIC) cohort study, which analyzed data from over 300,000 subjects and found no relationship between methionine intake and breast cancer risk (111416).
• Cisplatin-associated ototoxicity. It is unclear if oral D-methionine prevents cisplatin-associated ototoxicity. Details: A small clinical study in adults with cancer receiving cisplatin shows that taking D-methionine 100 mg/kg one hour prior to chemotherapy for up to 5 cycles prevents shifts in the hearing threshold at all four tested frequencies, compared with shifts occurring at three of the four tested frequencies in those receiving placebo (108039). The validity of these findings is limited by the lack of statistical comparison between groups.
• Colorectal cancer. It is unclear if high dietary intake of methionine reduces the risk of colorectal cancer. Details: A meta-analysis of observational research has found that higher dietary intake of methionine is associated with an 11% lower risk of colorectal cancer, a 23% lower risk of colon cancer, and a 12% lower risk of rectal cancer, when compared with lower intake of methionine. Increasing dietary intake of methionine by 1 gram daily is associated with a 11% reduction in the risk of colorectal cancer. Subgroup analyses have shown a significant inverse relationship between risk of colorectal cancer and dietary methionine intake in patients followed for at least 13.3 years, in Western populations, and in males (94094). There is some evidence that high dietary intake of methionine and folate might have a synergistic effect in decreasing the risk of colon cancer, especially in those with a family history of colon cancer and in those who consume large amounts of alcohol (9325,9326).
• Genital herpes. Oral L-methionine has only been evaluated in combination with other ingredients; its effects when used alone is unclear. Details: A small clinical study in patients with genital warts caused by herpes simplex virus (HSV) shows that taking acyclovir 200 mg five times daily for 5 days followed by 4 capsules of a combination product providing a total daily dose of L-methionine 200 mg, coenzyme Q10 50 mg, vitamin E 50 mg, and selenium 50 mcg for 90 days increases the rate of skin reepithelization by approximately 2 days and decreases the incidence of relapse when compared with acyclovir alone. Patients receiving combination therapy had a relapse rate of 13%, compared with a rate of 43% with acyclovir alone (94091).
• Herpes zoster (shingles). Oral L-methionine has only been evaluated in combination with other ingredients; its effects when used alone is unclear. Details: A small clinical study in patients with herpes zoster shows that taking acyclovir 800 mg five times daily for 10 days followed by 4 capsules of a combination product providing a total daily dose of L-methionine 200 mg, coenzyme Q10 50 mg, vitamin E 50 mg, and selenium 50 mcg for 90 days increases the rate of skin reepithelization by approximately 2 days, decreases the incidence of relapse, and decreases postherpetic neuralgia pain when compared with acyclovir alone. Patients receiving combination therapy had a relapse rate of 7%, compared with a rate of 44% with acyclovir alone (94091).
• Human papillomavirus (HPV). It is unclear if oral methionine is beneficial for the treatment of HPV lesions or for reducing the incidence of relapse. Details: A clinical study in patients aged 14 years or older with cutaneous warts caused by HPV shows that receiving conventional therapy in combination with one capsule of a product containing methionine, echinacea, inulin, taurine, vitamin A, vitamin C, coenzyme Q10, vitamin B3, zinc gluconate, and probiotics (Immuno Skin Plus tablets, Morgan Pharma S.r.l) daily for 20 days each month for 4 months reduces the number of warts at 6 months by about 5, with complete remission achieved in 86% of patients. The group receiving conventional therapy alone had a reduction in the number of warts by about 3, with complete remission achieved in 55% of patients. Conventional therapy consisted of either liquid nitrogen cryotherapy or topical therapy with salicylic acid 15% and lactic acid 15%. These findings are limited by the fact that patients in the combination therapy group had more warts at baseline when compared with those receiving conventional therapy alone (94092). Another small clinical study in patients with skin warts caused by HPV shows that cryotherapy followed by taking 4 capsules of a product containing a total dose of L-methionine 200 mg, coenzyme Q10 50 mg, vitamin E 50 mg, and selenium 50 mcg daily for 180 days increases the rate of complete recovery and decreases the incidence of relapse when compared with cryotherapy followed by placebo. At 180 days, 56% of patients in the active group experienced complete recovery, compared with 44% in the placebo group, and 30% of patients in the active group experienced a relapse, compared with 41% in the placebo group (94091). It is unclear if these effects are due to methionine, other ingredients, or the combination.
• Menopausal symptoms. It is unclear if oral L-methionine is beneficial for reducing hot flashes. Details: Preliminary clinical research in postmenopausal adults experiencing at least 5 hot flashes daily for the prior two months shows that taking L-methionine 1 gram twice daily for 12 weeks, then 2 grams twice daily for 8 weeks, does not improve hot flashes when compared with placebo (94090).
• Pancreatitis. Oral methionine has only been evaluated in combination with other ingredients; its effects when used alone is unclear. Details: A meta-analysis of eight randomized and nonrandomized clinical studies in patients with chronic or recurrent acute pancreatitis shows that taking a combination of methionine, selenium, vitamin E, vitamin C, and beta-carotene reduces pain when compared with placebo. However, when the two nonrandomized studies were excluded, the significant reduction in pain was lost. Daily doses of individual components studied included methionine 1.6-2.88 grams, selenium 300-600 mcg, vitamin E 188-280 mg, vitamin C 540-720 mg, and beta-carotene 12-54 mg. The study durations ranged from 10 weeks to 12 months (94095). The validity of these findings is limited by the heterogeneity of the included studies.
• Parkinson disease. Although there has been interest in using oral methionine for Parkinson disease, there is insufficient reliable information about the clinical effects of methionine for this purpose.
• Urinary tract infections (UTI). Oral methionine has only been evaluated in combination with other ingredients; its effects when used alone is unclear. Details: A low-quality observational study in patients with symptomatic UTI and culture-confirmed bacteriuria during pregnancy has found that taking a specific combination of methionine 800 mg, Hibiscus sabdariffa extract 200 mg, and Boswellia serrata 200 mg (Acidif Plus, Biohealth S.r.l) daily for one week increases the rate of negative urine cultures to 70% and symptom resolution to 63%, compared with 43% and 46%, respectively, in patients who increased fluid intake but did not take the combination product (97263). The validity of these findings is limited by the fact that the study groups were not comparable at baseline.
• Wound healing. Although there has been interest in using oral methionine for wound healing, there is insufficient reliable information about the clinical effects of methionine for this purpose. More evidence is needed to rate methionine for these uses.

(Read more about METHIONINE)

LIKELY EFFECTIVE

• Pellagra. Oral niacinamide is approved for the treatment of pellagra and niacin deficiency. Details: Niacinamide is FDA-approved for the prevention and treatment of niacin deficiency and pellagra. Niacinamide is sometimes preferred over niacin for this indication because it lacks the vasodilating and flushing effects of niacin (15,6243).

POSSIBLY EFFECTIVE

• Acne. Topical niacinamide seems to improve acne symptoms in some patients. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study shows that applying niacinamide 4% gel twice daily for 8 weeks is as effective as clindamycin 1% gel for reducing the number and severity of acne lesions. The niacinamide gel appears to be more effective in patients with oily skin than those with non-oily skin (93360). Other preliminary clinical research in adults with mild to moderate acne vulgaris shows that applying niacinamide 5% cream twice daily, 10 minutes after applying benzoyl peroxide 2.5% gel, for 12 weeks reduces the number of acne lesions, but not erythema or inflammation, when compared with benzoyl peroxide alone (107711). Niacinamide has also been studied in combination with other ingredients. In preliminary clinical research, oral niacinamide has been reported to improve acne when used in combination with zinc, copper, and folic acid (Nicomide) (25557), or in combination with azelaic acid, zinc, pyridoxine, copper, and folic acid (NicAzel, Elorac Inc.) (90800). In a small observational study, topical niacinamide 4% combined with gallic acid 1% and lauric acid 1% was associated with some improvement in acne (104931). It is unclear if the effects in these studies are due to niacinamide, other ingredients, or the combinations.
• Diabetes. Oral niacinamide does not seem to prevent the onset of type 1 diabetes, although it might slow its progression. Details: Although some older research has suggested that taking high-dose niacinamide can reduce the risk of type 1 diabetes in high-risk children (4874), results from higher quality, more rigorous clinical trials show that taking niacinamide up to 3 grams daily for 5 years does not prevent the onset of type 1 diabetes in first-degree relatives of patients with type 1 diabetes (4875,25553,25554). However, taking niacinamide 1.2 grams/m2 daily for 5 years may prevent the loss of beta-cell function in these patients (25555). Also, there is evidence showing that niacinamide can preserve residual beta-cell function in patients with newly diagnosed type 1 diabetes (4877,4878,4879,4880,25556). Clinical trials, including one placebo-controlled trial and one vitamin E-comparison study, show niacinamide can prolong the "honeymoon period" in those newly diagnosed with type 1 diabetes, when the pancreas is still capable of producing some insulin (4877,4878,4879,4880,25556). However, some scientists have raised concerns about potential induction of insulin resistance with short-term use of niacinamide 2 grams daily for 2 weeks (4881). Niacinamide has also been evaluated in adults with type 2 diabetes. A small clinical study in lean patients with type 2 diabetes who failed sulfonylurea therapy shows that taking niacinamide 500 mg three times daily for 6 months in addition to continuing insulin or a sulfonylurea increases C-peptide release and improves insulin secretion when compared with insulin alone (4882).
• Hyperphosphatemia. Adding oral niacinamide to standard treatment with phosphate binders further lowers blood levels of phosphorus in patients on hemodialysis. Details: A meta-analysis of nine small clinical trials in patients on hemodialysis with hyperphosphatemia who are using a phosphate binder shows that taking niacinamide 250-1500 mg daily for 2-6 months lowers serum phosphorus and parathyroid hormone levels when compared with placebo (98940) Another meta-analysis of two small clinical trials in the same patient population also shows that taking niacinamide, titrated from 500 mg to 1500 mg daily over 8 weeks, reduces serum phosphorus levels by about 0.9 mg/dL when compared with placebo (94188). Other clinical research in this population shows that taking modified-release niacinamide 250-1500 mg orally daily for 12-24 weeks also lowers serum phosphate and parathyroid levels when compared with placebo. However, these effects were not maintained at 40-52 weeks follow-up (107709,110499). In addition, this product was not compared with immediate-release niacinamide. Niacinamide has also been studied in place of phosphate binders. One small clinical study in patients on hemodialysis with hyperphosphatemia shows that taking niacinamide 500-1750 mg daily for 12 weeks, beginning 2 weeks after discontinuation of phosphate binders, decreases serum phosphorus levels by 1.5 mg/dL and intact parathyroid hormone levels by 50 pg/mL, without affecting calcium levels, when compared to baseline (25561).The validity of these findings is limited due to the lack of a control group.
• Osteoarthritis. Oral high-dose niacinamide might be beneficial for improving osteoarthritis symptoms. Details: Clinical research in patients with osteoarthritis shows that taking niacinamide 3 grams daily in six divided doses for 12 weeks improves joint flexibility, reduces inflammation, and modestly decreases use of nonsteroidal anti-inflammatory drugs (NSAIDs) when compared with placebo (4883).

POSSIBLY INEFFECTIVE

• Brain tumor. Adding high-dose oral niacinamide to chemotherapy does not seem to improve survival in patients with brain tumors. Details: Preliminary clinical research in patients with surgically resected brain tumors shows that treatment with radiotherapy, niacinamide, and carbogen does not improve survival when compared with radiotherapy alone or radiotherapy plus carbogen (11695,11696).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Actinic keratoses. It is unclear if oral or topical niacinamide is beneficial for reducing actinic keratoses. Research results are conflicting. Details: A large clinical trial in healthy Australian adults with actinic keratoses shows that taking a specific niacinamide product (Insolar, Blackmores) 500 mg twice daily for 12 months reduces the number of actinic keratoses by 13% when compared with placebo. The difference between the 2 groups was observed as early as 3 months after starting niacinamide (93362). Additionally, a small clinical study in healthy, older Australian adults with actinic keratoses shows that taking niacinamide (Nature's Own, Virginia) 500 mg once or twice daily for 4 months reduces the total number of actinic keratoses by 29% and 35%, respectively, when compared with placebo (93365). However, a large clinical trial in solid organ transplant recipients in Australia shows that taking a specific niacinamide product (Insolar, Blackmores) 500 mg twice daily for 6 months does not reduce the number of actinic keratoses when compared with placebo (113559). Also, a small clinical trial in kidney transplant recipients with actinic keratoses and a history of nonmelanoma skin cancer shows that taking niacinamide 500 mg twice daily for 12 months does not decrease the number of actinic keratoses when compared with placebo (113682). The study may have been inadequately powered to detect a difference between groups. Two small clinical studies conducted in Brazil in elderly adults with actinic keratoses shows that taking niacinamide 500 mg twice daily for 120 days or applying a cream containing niacinamide 5% twice daily for 56 days does not reduce the number of actinic keratoses when compared with placebo (107714,113684). Most studies were conducted in countries with high year-round ultraviolet radiation exposure, such as Australia and Brazil; results may not be readily extrapolated to populations in other geographic regions.
• Age-related cognitive decline. Although there is interest in using oral niacinamide for age-related cognitive decline, there is insufficient reliable information about the clinical effects of niacinamide for this purpose.
• Age-related macular degeneration (AMD). Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with early-stage age-related maculopathy shows that taking a combination of niacinamide 18 mg, vitamin E 20 mg, and lutein 15 mg daily for nearly a year improves retinal function when compared with no treatment (60134). It is unclear if this effect is due to niacinamide, other ingredients, or the combination.
• Aging skin. It is unclear if topical niacinamide improves symptoms of aging skin. Details: A small study in females with signs of facial photo-aging shows that applying niacinamide 5% cream to half of the face twice daily for 12 weeks improves blotchiness, the appearance of wrinkles, skin elasticity, and skin pigmentation when compared with applying placebo cream to the other half of the face (25551).
• Atopic dermatitis (eczema). It is unclear if topical niacinamide improves eczema symptoms. Details: A small clinical study in patients with atopic dermatitis and dry skin shows that applying niacinamide 2% cream twice daily for 8 weeks decreases skin water loss and improves skin hydration when compared with using a white petrolatum moisturizer (25560). A moderate-sized clinical study in adults with mild atopic dermatitis (AD) shows that applying a specific niacinamide containing body emollient (Bioderma Atoderm PP Baume, Bioderma Cosmetics Trading Co., Ltd.) 250 grams weekly, applied twice daily for 28 days with or without pre-cleansing with a specific niacinamide containing gel wash (Atoderm Intensive Gel Moussant, Bioderma Cosmetics Trading Co., Ltd.), improves AD severity, itching, trans-epidermal water loss, skin water content, and dermatological quality of life when compared with a control emollient and water-only skin cleansing. Additionally, using both the niacinamide containing emollient and cleansing gel improves trans-epidermal water loss and skin water content sooner when compared with niacin containing emollient only (113681). However, the study may have been inadequately powered and too short in duration to detect additional differences between the 2 niacinamide groups.
• Attention deficit-hyperactivity disorder (ADHD). Oral niacinamide has only been evaluated in combination with other vitamins; its effect when used alone is unclear. Details: A small clinical study in children with ADHD shows that taking a maximum of niacinamide 3 grams, ascorbic acid 3 grams, calcium pantothenate 1.2 grams, and pyridoxine 600 mg daily for 3 months seems to improve behavior in 29% of participants when compared with baseline (9957). The validity of this finding is limited by the lack of a comparator group.
• Bladder cancer. Oral niacinamide has only been evaluated in combination with carbogen for improving survival in advanced bladder cancer; its effect when used alone is unclear. Details: A phase II clinical study in patients with locally advanced bladder cancer shows that adding inhaled carbogen and oral niacinamide 40-60 mg/kg about 2 hours before radiotherapy shows a trend to improved survival at 3 years when compared with inhaled carbogen and radiotherapy (25558), and a larger phase III study shows that carbogen and oral niacinamide improves 3-year survival by about 13% when compared with radiotherapy alone (93366). An observational follow-up of the phase III study found a trend to increased survival at 5 years in the carbogen and niacinamide group when compared with radiotherapy alone. And in a subgroup of patients with tumor necrosis, the 5-year survival was significantly greater with carbogen and niacinamide when compared with radiotherapy alone (93356). It is unclear if these effects are due to niacinamide, carbogen, or the combination.
• Child growth. It is unclear if oral niacinamide improves child growth. Details: Preliminary clinical research in children in rural Tanzania shows that supplementing niacinamide orally from birth to 18 months of age does not improve length-for-age, weight-for-age, or head circumference when compared with control. Niacinamide was initially supplemented to breast-feeding mothers, 250 mg daily, until 6 months of age, followed by 100 mg daily taken by the child until 18 months of age (107713).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral niacinamide is beneficial for COVID-19. Details: Observational research in adults with acute kidney injury secondary to coronavirus disease-19 infection has found that taking niacinamide 1000 mg orally daily for 7 days is associated with a 55% lower risk of mortality when compared with control. However, taking niacinamide was not associated with a lower risk of renal replacement therapy (110500).
• Cutaneous lupus erythematosus (CLE). It is unclear if topical niacinamide is beneficial for CLE. Details: Preliminary clinical research in adults with discoid lupus erythematosus, a type of CLE, shows that applying topical niacinamide 2% to 4% twice daily for 12 weeks modestly improves lesion scores, but not quality of life scores, when compared with placebo. However, the study may have been inadequately powered to detect a difference between groups (110498).
• Depression. Although there is interest in using oral niacinamide for depression, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Diabetic neuropathy. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with diabetic polyneuropathy shows that taking a specific combination product (Cytoflavin, Polysan) containing niacinamide, inosine, riboflavin, and succinate daily for 12 weeks improves symptom scores, including paresthesia and numbness scores, when compared with placebo. The therapy was first administered intravenously, providing niacinamide 200 mg, inosine 400 mg, riboflavin 40 mg, and succinate 2000 mg daily for 10 days, followed by an oral formulation providing niacinamide 100 mg, inosine 200 mg, riboflavin 20 mg, and succinate 1200 mg daily for the remainder of the study (110503).
• Erythema. Topical niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: There is interest in using niacinamide to reduce the side effects of topical tretinoin, including erythema. A small preliminary clinical study in patients using isotretinoin for acne shows that applying a specific cream (Sebiaclear Hydra, SVr Laboratoire Dermatologique) containing niacinamide 5% and omega-ceramides 8% twice daily for 6 months reduces isotretinoin-induced erythema, dryness, and itching of the skin when compared with a glycerin placebo (98938). It is not clear if this effect is due to niacinamide, omega-ceramides, or the combination.
• Head and neck cancer. Oral niacinamide has only been evaluated in combination with carbogen for improving survival in laryngeal cancer; its effect when used alone is unclear. Details: A phase III clinical trial in patients with laryngeal cancer shows that treatment with accelerated radiotherapy plus carbogen and niacinamide 60 mg/kg taken orally 1-1.5 hours prior to each fraction of radiation improves local tumor control, but does not improve overall survival or 5-year disease-free survival, when compared with accelerated radiotherapy alone. In a subgroup of patients with hypoxic tumors, anemia, or high expression of epidermal growth factor receptor, receiving niacinamide and carbogen seems to improve both survival and tumor control when compared with radiotherapy alone (93358,93359,93363).
• Melasma. It is unclear if topical niacinamide improves melasma. Details: A small clinical study in female adults with melasma shows that applying a specific niacinamide 10% serum (Bo leda, Shanghai Ruizhi Medical Technology Co., Ltd) twice daily after skin cleansing for 16 weeks improves melasma area and severity, pigmented spots, and skin texture when compared with control. Both groups were also treated with salicylic acid 30% throughout the study (113683). Topical niacinamide has also been studied in patients with hyperpigmentation. A small clinical study in Japanese females with uneven facial hyperpigmentation shows that applying niacinamide 5% moisturizer to the face twice daily reduces hyperpigmentation and increases skin lightness after 4 weeks when compared with placebo moisturizer. However, further improvements are not observed after another 4 weeks of treatment (25552). Another small clinical study in Korean females with uneven facial hyperpigmentation shows that applying a moisturizer containing niacinamide 2% plus tranexamic acid 2% (Regederm RX White Project, Aestura) twice daily for 8 weeks reduces skin pigmentation by about 9% when compared with a placebo cream (93361).
• Non-Hodgkin lymphoma. It is unclear if adding oral niacinamide to chemotherapy reduces relapses of refractory lymphoma. Details: One small clinical study in patients with relapsed or refractory lymphoma shows that 24% of patients achieve complete or partial remission and 57% achieve disease stabilization when compared with baseline, following treatment with vorinostat 400 mg daily and niacinamide titrated from 20 mg/kg to 100 mg/kg over the first 14 days of a 21-day cycle for up to 18 cycles (93355). It is unclear how these outcomes compare to using vorinostat alone, or to other control treatments.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral niacinamide is beneficial for NAFLD. Details: Preliminary clinical research in adults with NAFLD and diabetes shows that taking a specific niacinamide product (Nature's Life) 1000 mg orally daily for 12 weeks does not improve liver function tests, liver steatosis, or liver fibrosis when compared with no intervention. However, some quality of life domain scores were moderately improved. However, the study may have been inadequately powered to detect a difference between groups (110502).
• Nonmelanoma skin cancer. It is unclear if oral or topical niacinamide reduces the risk of nonmelanoma skin cancer. Details: A meta-analysis of 4 clinical trials in adults shows that taking niacinamide 500 mg twice daily for 4-12 months does not reduce the risk of nonmelanoma skin cancer when compared with placebo. This analysis also shows no effect of niacinamide on the risk of basal cell carcinoma and squamous cell carcinoma (113560). However, there was high heterogeneity across the studies due to differences in patient populations and mixed results overall. Two studies included in the analysis show that niacinamide, including a specific niacinamide product (Nature's Own, Virginia), reduces the risk of nonmelanoma skin cancer in immunocompetent adults when compared with placebo (93362,93365). One was a large clinical trial that shows taking a specific niacinamide product (Insolar, Blackmores) 500 mg twice daily for 12 months reduces the rate of new nonmelanoma skin cancer by 23%, but it does not reduce the risk of not recurrent nonmelanoma skin cancers, when compared with placebo. However, this reduced risk appears to be transient. Follow up 6 months after niacinamide was discontinued showed no difference between groups (93362). The 2 other studies analyzed, including a large trial using a specific niacinamide product (Insolar, Blackmores), were conducted in transplant recipients showed no reduced risk of nonmelanoma skin cancer when compared with placebo (113560,113559). All studies were conducted in Australia; it is unclear if these results can be extrapolated to other geographical regions with different background ultraviolet radiation exposure and skin cancer rates. A previous meta-analysis of 5 clinical studies shows taking niacinamide 500-1000 mg daily for 6-12 months or applying niacinamide 1% twice daily for 6 months decreases the rate of basal cell and cutaneous squamous cell carcinomas by 54% and 52%, respectively when compared with control. Niacinamide was only administered topically in 1 of the 5 studies and only reduced risk of cutaneous squamous cell carcinoma (110497).
• Premenstrual syndrome (PMS). Although there is interest in using oral niacinamide for PMS, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Pruritus. It is unclear if oral niacinamide reduces pruritus in patients with kidney failure. Details: A small clinical study in patients with pruritus due to kidney failure shows that taking niacinamide sodium 500 mg twice daily for 4 weeks does not reduce pruritus severity when compared with placebo (93364). This study is limited due to small size and short study duration.
• Psoriasis. It is unclear if oral niacinamide is beneficial for psoriasis. Details: Preliminary clinical research in adults with mild to moderate psoriasis shows that applying niacinamide 4% cream topically twice daily for 12 weeks improves psoriasis scores by 31% when compared with baseline. The validity of these results is limited by the lack of a comparator group (110501).
• Rosacea. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that 71% of adult and adolescent patients with rosacea who take a combination product (Nicomide) containing niacinamide 750 mg, zinc 25 mg, copper 1.5 mg, and folic acid 500 mcg once or twice daily report improvement in appearance after 4 weeks when compared to baseline (25557). The validity of these findings is limited by the lack of a control group.
• Schizophrenia. Although there is interest in using oral niacinamide for schizophrenia, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Seborrheic dermatitis. It is unclear if topical niacinamide is beneficial for reducing seborrheic dermatitis symptoms. Details: One small clinical study in patients with seborrheic dermatitis shows that applying niacinamide 4% cream once daily for 12 weeks reduces the severity of symptoms such as redness and scaling by 75%, compared with a 35% reduction when using a placebo cream (93357). More evidence is needed to rate niacinamide for these uses.

(Read more about NIACINAMIDE)

EFFECTIVE

• Pantothenic acid deficiency. Taking pantothenic acid 5-10 mg daily is effective for treating and preventing pantothenic acid deficiency (15).

POSSIBLY INEFFECTIVE

• Radiation dermatitis. Topical dexpanthenol does not seem to be beneficial for preventing or treating radiation dermatitis. Details: Applying dexpanthenol, an analog of pantothenic acid, twice daily to areas of irradiated skin does not seem to reduce erythema, desquamation, itching, or pain following radiation treatment (7192). Also, applying dexpanthenol 0.5% cream (Bepanthen, Hoffmann LaRoche ) daily during radiation therapy and for 2 weeks after completing radiation therapy is less effective than methylprednisolone aceponate 0.1% cream (Advantan) at reducing radiation-induced skin irritation (67779).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Oral or topical pantothenic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In adults with mild to moderate acne, clinical research shows that taking a specific supplement (Pantothen, Avilan Marketing LLC) providing pantothenic acid 1.1 grams twice daily in addition to other B vitamins for 12 weeks modestly reduces total and non-inflammatory lesion counts when compared with placebo (105188). Also, in adolescents or young adults with mild to moderate acne, preliminary clinical research shows that topical application with a gel containing D-panthenol 4%, hydrogen peroxide 4%, and salicylic acid 0.5% once daily for 60 days modestly reduces acne lesions when compared with baseline (105189). The validity of this finding is limited by the lack of a comparator group.
• Alcoholism. Although there is interest in using oral pantothenic acid for improving recovery from alcoholism, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Allergic rhinitis (hay fever). Although there is interest in using oral pantothenic acid for allergic rhinitis, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Alopecia areata. Pantothenic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy adults with diffuse hair loss shows that intramuscular administration of dexpanthenol 250 mg and biotin 5 mg once weekly for 6 weeks reduces hair fall count at weeks 1 and 8, but only increases hair density at week 1, when compared to baseline (111366). The validity of these findings is limited by the study's small size, short duration, and lack of comparator group.
• Anxiety. Although there is interest in using oral pantothenic acid for anxiety, there is insufficient reliable information about the clinical effects of pantothenic acid for this purpose.
• Asthma. Although there is interest in using oral pantothenic acid for asthma, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Athletic performance. Although there is interest in using oral pantothenic acid to improve athletic performance, there is insufficient reliable information about the clinical effects of pantothenic acid for this purpose.
• Attention deficit-hyperactivity disorder (ADHD). Oral pantothenic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some small outdated clinical studies in children diagnosed with hyperkinesis suggest that taking calcium pantothenate 1.2 grams, alone or in combination with niacinamide, ascorbic acid, and pyridoxine, does not improve symptoms of hyperactivity when compared with placebo (3351,9957). It is unclear what effects pantothenic may have, if any, in children with a modern diagnosis of ADHD.
• Atopic dermatitis (eczema). It is unclear if topical pantothenic acid is beneficial in infants or children with atopic dermatitis. Details: One preliminary clinical trial in infants and children with stable mild atopic dermatitis shows that topical application of an emollient containing panthenol (Bepanthen, SensiDaily, Bayer Consumer Care AG) for 3 months is as effective as a reference emollient for reducing symptoms and preventing a flare. However, the efficacy of the reference emollient (Stelatopia Emollient Cream, Mustela; Laboratoires Expanscience) is unclear based on available preliminary clinical research (105190).
• Autism spectrum disorder. Although there is interest in using oral pantothenic acid for autism spectrum disorder, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Carpal tunnel syndrome. Although there is interest in using oral pantothenic acid for carpal tunnel syndrome, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Cheilitis. Topical pantothenic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, open-label study in adults with mild-to-moderate cheilitis shows that applying a specific lip care product containing pantothenic acid and bisabolol (Eucerin Aquaphor SOS lip care) at least twice daily for 8 weeks reduces cheilitis severity scores by 5 points on a 12 point scale assessing erythema, scale, fissure, and inflammation when compared to baseline (114549). The validity of this finding is limited by the small study size and lack of a comparator group. Additionally, it is unclear if this effect is due to pantothenic acid, bisabolol, or the combination.
• Chronic fatigue syndrome (CFS). Although there is interest in using oral pantothenic acid for CFS, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Conjunctivitis. Although there is interest in using oral or ocular pantothenic acid for conjunctivitis, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Constipation. It is unclear if oral or intramuscular dexpanthenol is beneficial for constipation. Details: Preliminary clinical research shows that administering dexpanthenol (Bepanthene), an analog of pantothenic acid, 400 mg orally or 500 mg intramuscularly daily for 5 days decreases the time to a bowel movement in patients with chronic or occasional constipation when compared with an oral placebo (67822).
• Dandruff. Although there is interest in using oral or topical pantothenic acid for dandruff, is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Depression. Although there is interest in using oral pantothenic acid for depression, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Diaper rash. Although there is interest in using topical pantothenic acid for diaper rash, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Dry eye. Although there is interest in using ocular pantothenic acid for dry eye, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Dry skin. It is unclear if topical dexpanthenol is beneficial for patients with dry skin. Details: A small, open-label study in healthy adults with dry skin shows that cleansing the skin with a dexpanthenol-containing liquid cleanser (DCLC, Bepanthen SensiControl Daily Gentle Body Wash) daily for 4 weeks increases stratum corneum hydration by 17% without affecting skin barrier function, pH, or microbiome when compared to baseline (111262). The validity of these findings is limited by the lack of blinding and a comparator group.
• Epilepsy. Although there is interest in using oral pantothenic acid for epilepsy, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Eye trauma. It is unclear if ocular dexpanthenol is beneficial for eye trauma. Details: Some preliminary clinical research shows that using eyedrops containing dexpanthenol 5%, a derivative of pantothenic acid, two drops four times daily for 28 days following surgery for retinal detachment reduces eye pain and discomfort when compared with placebo drops (67783). However, using a specific dexpanthenol 5% ointment (Bepanthen) does not seem to improve corneal epithelial wound healing following phototherapeutic keratectomy when compared with placebo (67801).
• Heart failure. Although there is interest in using oral pantothenic acid for heart failure, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Herpes zoster (shingles). Although there is interest in using oral or topical pantothenic acid for shingles, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Insomnia. Although there is interest in using oral pantothenic acid for insomnia, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Laser skin resurfacing. It is unclear if topical dexpanthenol or pantothenic acid can reduce adverse effects after laser skin resurfacing procedures. Details: A preliminary clinical study shows that use of a dexpanthenol-containing ointment (Bepanthen Wound Healing Ointment, Bayer) once daily modestly reduces the diameter of lesions up to 3 days after fractional carbon dioxide laser resurfacing when compared with petroleum jelly (105743). Also, applying a specific cream (Cicaplast Baume B5 cream, L'Oreal) containing panthenol 5%, madecassoside, copper, zinc, and manganese to one side of the face for 28 days reduces decrustation time by approximately one day when compared with a control emollient. Redness and swelling were lower at 3 days, but there was no difference in pain and burning (105742). It is unclear if these effects are due to pantothenic acid, other ingredients, or the combination.
• Multiple sclerosis (MS). Although there is interest in using oral pantothenic acid for MS, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Muscular dystrophy. Although there is interest in using oral pantothenic acid for muscular dystrophy, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Nipple fissures. Although there is interest in using topical pantothenic acid for nipple fissures, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Obesity. Although there is interest in using oral pantothenic acid for obesity, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Pain (chronic). It is unclear if oral or topical pantothenic acid is beneficial for the management of various forms of chronic pain. Details: Although there is interest in using oral or topical pantothenic acid for various forms of chronic pain, including neuropathy and arthritis, there is limited information available about the clinical effects of pantothenic acid for this purpose. One review of preliminary clinical research found that calcium pantothenate does not reduce symptoms of arthritis in patients with rheumatoid arthritis or osteoarthritis (10433).
• Parkinson disease. Although there is interest in using oral pantothenic acid for Parkinson disease, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Poison oak and poison ivy dermatitis. Although there is interest in using topical pantothenic acid for poison ivy dermatitis, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Postoperative pain. It is unclear if oral pantothenic acid is beneficial for postoperative pain. Details: In post-tonsillectomy patients aged 5-12 years, preliminary clinical research shows that taking pastilles containing dexpanthenol (Bepanthene, Bayer) 100 mg three times daily reduces pain when compared with placebo. Postoperative pain was modestly reduced at 1, 3, 7, and 14 days after surgery (105191).
• Postoperative sore throat. It is unclear if pantothenic acid lozenges are beneficial for postoperative sore throat. Details: Preliminary clinical research shows that taking two lozenges containing dexpanthenol, an analog of pantothenic acid, 200 mg 30 minutes prior to general anesthesia reduces the incidence and severity of postoperative sore throat when compared with a benzydamine hydrochloride or placebo spray (67792).
• Pregnancy-related leg cramps. Although there is interest in using oral pantothenic acid for pregnancy-related leg cramps, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Premenstrual syndrome (PMS). Although there is interest in using oral pantothenic acid for PMS, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Respiratory tract infections. Although there is interest in using oral pantothenic acid for respiratory tract infections, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Rhinosinusitis. It is unclear if nasal dexpanthenol is beneficial for rhinosinusitis. Details: Preliminary clinical research shows that using a nasal spray (MarPlus) containing dexpanthenol, an analog of pantothenic acid, on the first, second, fourth, and sixth week after endoscopic sinus surgery reduces nasal discharge, but not other symptoms associated with chronic rhinosinusitis, when compared with saline nasal spray (67808).
• Skin irritation. It is unclear if topical dexpanthenol is beneficial for preventing or treating skin irritation due to sodium lauryl sulfate. Details: Preliminary clinical research shows that applying dexpanthenol (Bepanthol Handbalsam), an analog of pantothenic acid, twice daily for 26 days does not prevent sodium lauryl sulfate-induced skin irritation (67785). However, dexpanthenol may be effective for treating skin irritation caused by sodium lauryl sulfate. Use of an ointment containing dexpanthenol 1% to 5% twice daily for up to 30 days following skin exposure to sodium lauryl sulfate seems to reduce skin water loss, skin roughness, and skin inflammation when compared to control (67802,67806).
• Ulcerative colitis. Although there is interest in using oral or rectal pantothenic acid for ulcerative colitis, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Vertigo. Although there is interest in using oral pantothenic acid for vertigo, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Wound healing. Preliminary clinical research suggests that oral dexpanthenol might be beneficial for wound healing. Details: In post-tonsillectomy patients aged 5-12 years, preliminary clinical research shows that taking pastilles containing dexpanthenol (Bepanthene, Bayer) 100 mg three times daily improves wound healing when compared with placebo. Depending on the type of surgery, wound healing occurred in 2.3-2.9 times as many patients within 7 days of surgery, and in 13% to 35% more patients within 14 days, when compared with placebo (105191). More evidence is needed to rate pantothenic acid for these uses.

(Read more about PANTOTHENIC ACID)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cancer. Although there has been interest in using oral papain for cancer, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Dental caries. It is unclear if topical papain gel is beneficial for reducing procedure time or pain in children having caries removed by a dentist. Details: A small clinical study in children 3-9 years of age with dental caries shows that application of a specific papain gel (Brix3000, Brix Medical Science) 3000 U/mg during atraumatic restorative treatment (ART) by a dentist actually increases the time required to remove caries tissue, with no effect on pain, when compared with ART alone (107434).
• Diabetic foot ulcers. Although there has been interest in using topical papain for diabetic foot ulcers, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Exercise-induced muscle soreness. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy males shows that taking a combination enzyme tablet containing papain 50 mg, trypsin 75 mg, bromelain 50 mg, amylase 10 mg, lipase 10 mg, lysosome 10 mg, and chymotrypsin 2 mg, four times in one day before downhill running, improves recovery of contractile muscle function and decreases muscle soreness when compared with placebo (67838). It is unclear if these findings are due to papain, other ingredients, or the combination.
• Herpes zoster (shingles). Although there has been interest in using oral papain for shingles, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Insect bite. It is unclear if topical papain is beneficial in individuals with fire ant stings. Details: A small clinical study in individuals with fire ant stings shows that applying gauze soaked with a specific papain-containing meat tenderizer (Adolph's meat tenderizer) to the sting for 20 minutes does not reduce pain or itching when compared with placebo (67845).
• Intestinal parasite infection. Although there has been interest in using oral papain for intestinal parasite infections, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Jellyfish stings. It is unclear if topical papain is beneficial in individuals with jellyfish stings. Details: A small clinical study in individuals with jellyfish stings shows that submerging affected skin into a solution with a papain-containing meat tenderizer (Adolph's meat tenderizer), starting two minutes after a jellyfish sting and continuing for at least 20 minutes, is less effective than hot water alone in decreasing pain caused by the jellyfish sting (67835).
• Ocular floaters. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in patients with symptomatic ocular floaters shows that taking 1, 2, or 3 capsules daily of an oral mixed fruit enzyme product containing papain 95 mg, ficin 95 mg, and bromelain 190 mg for 3 months leads to 55%, 63%, and 70% of floaters completely disappearing, respectively, when compared to baseline, as well as significant improvements when compared with vitamin C. Additionally, in patients with vitreous hemorrhage-induced symptomatic ocular floaters, taking 3 capsules daily of the same mixed fruit enzyme product for 3 months leads to 56% of floaters completely disappearing and improves visual acuity when compared to baseline, as well as significant improvements when compared with vitamin C (111650). It is unclear if these effects are due to papain, other ingredients, or the combination.
• Pressure ulcers. Although there has been interest in using topical papain for pressure ulcers, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Radiation dermatitis. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients receiving pelvic radiotherapy shows that taking three capsules of a specific combination product (Wobe-Mugos E, Mucos Pharma) containing papain 100 mg, trypsin 40 mg, and chymotrypsin 40 mg per capsule, four times daily, beginning 3 days prior to radiotherapy and continuing until the last day of therapy, does not attenuate skin deterioration when compared with placebo (67834). However, another small, open-label clinical study in patients with uterine carcinoma shows that taking three capsules of the same combination product four times daily, beginning 7 days before radiotherapy and continuing for 9 weeks, reduces skin reactions when compared with control (67831). It is unclear if these findings are due to papain, other ingredients, or the combination.
• Radiation-induced cystitis. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with uterine carcinoma receiving radiotherapy shows that taking three capsules of a specific combination product (Wobe-Mugos E, Mucos Pharma) containing papain 100 mg, trypsin 40 mg, and chymotrypsin 40 mg per capsule, four times daily, beginning 7 days before radiotherapy and continuing for 9 weeks, reduces genitourinary symptoms when compared with control (67831).
• Radiation-induced nausea and vomiting. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients receiving pelvic radiotherapy shows that taking three capsules of a specific combination product (Wobe-Mugos E, Mucos Pharma), containing papain 100 mg, trypsin 40 mg, and chymotrypsin 40 mg per capsule, four times daily, beginning 3 days prior to radiotherapy and continuing until the last day of therapy, does not reduce radiation-related nausea or vomiting when compared with placebo (67834).
• Tonsillopharyngitis. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Two small clinical studies in patients with pharyngitis and/or tonsillitis shows that use of throat lozenges containing papain 2 mg, lysozyme 5 mg, and bacitracin 200 IU daily for 4 days reduces pain and inflammation of the throat and lymph nodes when compared with placebo or disinfectant alone (964,968). It is unclear if these findings are due to papain, other ingredients, or the combination.
• Traumatic oral ulcers. Although there has been interest in using topical papain for traumatic oral ulcers, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Venous leg ulcers. Although there has been interest in using topical papain for venous leg ulcers, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Wound healing. Topical papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with purulent wounds shows that applying papain 1% solution plus dimethylsulfoxide (DMSO) followed by phonophoresis, a process by which ultrasound is used to increase topical drug delivery, improves wound healing when compared to baseline (67843). The validity of this finding is limited by the lack of a comparator group. Also, it is unclear if these findings are due to papain, DMSO, or the combination. More evidence is needed to rate papain for these uses.

(Read more about PAPAIN)

EFFECTIVE

• Sunburn. Topical PABA prevents sunburn. Details: PABA is an FDA-approved sunscreen (266,8952). PABA seems to be effective during sweating, but not when skin is immersed in water (272). PABA sunscreens can be applied topically in concentrations of 1% to 15% (272).

POSSIBLY EFFECTIVE

• Peyronie disease. Low quality clinical research shows that oral PABA improves Peyronie disease symptoms. Details: PABA is FDA-approved for use in this condition. Clinical research shows that taking the specific PABA product (POTABA, Glenwood LLC.), 3 grams orally four times a day for 8-12 months can reduce penile curvature and deterioration when compared with placebo (1067,8951,67982).

POSSIBLY INEFFECTIVE

• Scleroderma. Clinical research is conflicting, but suggests that oral PABA is not effective for treating scleroderma. Details: Although PABA is FDA-approved for scleroderma, as well as morphea, a localized form of scleroderma, evidence supporting its use is limited. Some retrospective studies suggest it might help for some symptoms of scleroderma, but higher quality evidence shows that it is not beneficial (1071,1073,1074,1075).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Although there has been interest in using oral PABA for aging skin, there is insufficient reliable information about the clinical effects of PABA for this purpose.
• Constipation. Although there has been interest in using oral PABA for constipation, there is insufficient reliable information about the clinical effects of PABA for this purpose.
• Headache. Although there has been interest in using oral PABA for headache, there is insufficient reliable information about the clinical effects of PABA for this purpose.
• Herpes keratitis. Although there has been interest in using ophthalmic PABA for herpes keratitis, there is insufficient reliable information about the clinical effects of PABA for this purpose.
• Infertility. Although there has been interest in using oral PABA for infertility, there is insufficient reliable information about the clinical effects of PABA for this purpose.
• Inflammatory myopathies. It is unclear if oral PABA is beneficial in patients with inflammatory myopathies. Details: PABA is FDA-approved for use in dermatomyositis, a type of inflammatory myopathy, but there is limited evidence to support this use (10). PABA is taken as 12 grams orally daily in 4 to 6 divided doses in adults or 220 mg/kg orally daily in 4 to 6 divided doses in children (10).
• Pemphigus. It is unclear if oral PABA is beneficial in patients with pemphigus. Details: PABA is FDA-approved for use in pemphigus, but there is limited evidence to support this use (10). PABA is taken as 12 grams orally daily in 4 to 6 divided doses in adults or 220 mg/kg orally daily in 4 to 6 divided doses in children (10).
• Systemic lupus erythematosus (SLE). Although there has been interest in using oral PABA for SLE, there is insufficient reliable information about the clinical effects of PABA for this purpose.
• Vitiligo. Although there has been interest in using oral PABA for vitiligo, there is insufficient reliable information about the clinical effects of PABA for this purpose. More evidence is needed to rate PABA for these uses.

(Read more about PARA-AMINOBENZOIC ACID (PABA))

EFFECTIVE

• Hypokalemia. Oral or intravenous potassium can treat and prevent hypokalemia. Details: Administering potassium orally or intravenously is effective for treating and preventing hypokalemia (15,107970). Oral potassium 20 mEq (780 mg of elemental potassium) is typically taken once daily to prevent hypokalemia (15,95010). Oral potassium 40-100 mEq (1560-3900 mg of elemental potassium) is typically taken in 2-5 divided doses daily to treat hypokalemia (95010). Doses should be limited to 40 mEq (1560 mg of elemental potassium), and the total dose should not exceed 200 mEq (7800 mg of elemental potassium) in 24 hours (95010). Potassium supplementation and route of administration should be individualized based on serum potassium level and patient status (15,107970).

LIKELY EFFECTIVE

• Hypertension. Oral potassium, via dietary intake or supplementation, reduces blood pressure. Details: Population research has found that higher dietary potassium consumption is associated with a lower risk of developing hypertension (1310,8817,69512). Additionally, most clinical research shows that potassium, taken orally as part of the diet or as a supplement, reduces systolic blood pressure by about 3-9.5 mmHg and diastolic blood pressure by about 2-6.4 mmHg in patients with or without hypertension (3385,92104,92106,95624,107974). In most of these studies, daily intake of potassium typically ranged from about 1500-7800 mg, with the most common intake being about 2340-2540 mg daily (92104,95624). However, some research shows that taking potassium does not lower systolic or diastolic blood pressure (69541,69550,107966). Differences in the patient populations, potassium intake, and salt intake could have contributed to the conflicting results. Potassium seems to be more effective for people with hypertension, low potassium levels, high daily sodium intake, and for Black adults (3384,3385,3386,92104,92106). Some research also shows that the greatest blood pressure-lowering effects of potassium occur at doses of about 3900-7800 mg daily (95624). A meta-analysis of clinical trials using a novel computational technique to assess both potassium intake and excretion suggests that the optimal blood pressure reduction occurs when taking about 1500 mg supplemental potassium daily or an overall intake of 4500-6500 mg potassium daily (105448). This analysis is limited by the heterogeneity and short duration of the included trials. There is also interest in utilizing low-sodium, high-potassium food substitutes to treat hypertension. Research shows that using salt substitutes containing 25% to 30% potassium chloride reduces systolic and diastolic blood pressure by 3-4.6 mmHg and 1 mmHg, respectively, when compared with regular table salt (107971,107976). In 2017, the American College of Cardiology and the American Heart Association (ACC/AHA) published guidelines recommending that patients with hypertension consume 3500-5000 mg of potassium daily (95680). This intake of potassium is expected to lower systolic blood pressure by about 4-5 mmHg in patients with hypertension and by about 2 mmHg in normotensive patients (3385). Although potassium supplements and dietary potassium both seem to be beneficial, the guidelines recommend getting potassium from dietary sources, since potassium-rich diets are usually heart-healthy (95680). Additionally, the US Food and Drug Administration (FDA) has determined that foods containing at least 350 mg potassium and that are low in sodium, saturated fat, and cholesterol can state that "diets containing foods that are good sources of potassium and low in sodium may reduce the risk of high blood pressure and stroke" (1310,8817).
• Kidney stones (nephrolithiasis). Oral prescription potassium citrate reduces the risk of kidney stone recurrence. It is unclear if non-prescription potassium citrate would be beneficial. Details: The American Urological Association (AUA) recommends potassium citrate therapy for patients with recurrent calcium stones and low urinary citrate, those with recurrent calcium or calcium oxalate stones without current metabolic abnormalities, and those with uric acid or cystine stones. The citrate component reduces urine calcium excretion and increases urine citrate and urine pH, which in turn alleviates crystal growth, formation, and aggregation. Sodium citrate may also be used to prevent stone recurrence; however, due to sodium's propensity to increase urine calcium excretion, potassium citrate remains the preferred salt formulation (107972). It is important to note that potassium citrate supplements are not equivalent to prescription potassium citrate products. Dose and duration of treatment is determined by a healthcare professional and individualized based on a patient's urinary citrate levels (107975,107989). Serum potassium levels should be monitored prior to starting potassium citrate, within 2 weeks of treatment initiation, and every 12 months (107975).

POSSIBLY EFFECTIVE

• Cardiovascular disease (CVD). Eating foods high in potassium and low in sodium might reduce the risk of cardiovascular disease. It is unclear if taking potassium supplements has the same benefit. Details: Large population studies in adults without prior CVD have found that higher dietary potassium intake is associated with a lower risk of cardiovascular events (109395,109399). One study found that daily potassium intake of about 3300 mg is associated with a 13% reduction in CVD risk when compared with intake of about 1920 mg (109399). The other study found that each additional 1000 mg of daily urinary potassium excretion, which is a marker of dietary intake, is associated with an 18% reduction in CVD risk (109395). Another observational study in over 15,000 adults with history of stroke or hypertension shows that replacing regular table salt with a substitute product containing 75% sodium chloride and 25% potassium chloride for an average of 5 years decreases the rate of stroke, major cardiovascular events, or death (107976). High quality clinical trials are needed to confirm this association. The US Food and Drug Administration (FDA) has determined that foods containing at least 350 mg potassium and that are low in sodium, saturated fat, and cholesterol can state that "diets containing foods that are good sources of potassium and low in sodium may reduce the risk of high blood pressure and stroke" (1310,8817).
• Stroke. Eating foods high in potassium and low in sodium might reduce the risk of stroke. It is unclear if taking potassium supplements has the same benefit. Details: Higher dietary intake of potassium seems to be associated with a lower risk of stroke. Population research has found that increasing dietary potassium intake by 1-1.5 grams daily is associated with up to a 20% reduced risk of stroke (92105,92107). Some population research has found that higher supplemental intake of potassium is associated with a 29% reduced risk of ischemic stroke. However, supplemental potassium intake is not found to be associated with a lower risk of hemorrhagic or total stroke (92107). An observational study in over 15,000 adults with history of stroke or hypertension shows that replacing regular table salt with a substitute product containing 75% sodium chloride and 25% potassium chloride for an average of 5 years decreases the rate of stroke, major cardiovascular events, or death (107976). High quality clinical trials are needed to confirm this association. The US Food and Drug Administration (FDA) has determined that foods containing at least 350 mg potassium and that are low in sodium, saturated fat, and cholesterol can state that "diets containing foods that are good sources of potassium and low in sodium may reduce the risk of high blood pressure and stroke" (1310,8817).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Dental hypersensitivity. It is unclear if topical potassium improves dental hypersensitivity. Details: One meta-analysis of clinical research shows that using a dentifrice containing 5% potassium nitrite reduces dentin sensitivity when compared with a dentifrice that does not contain potassium nitrite (69549). Other clinical research published in a systematic review shows that potassium-containing toothpastes might reduce dentin sensitivity more than controls that do not contain potassium. However, these toothpastes might be less effective than other active toothpastes, such as those containing sodium monofluorophosphate, and the effect may result from a placebo effect, since the mechanism of action of potassium is unclear (69456).
• Diabetes. It is unclear if increasing dietary potassium reduces the risk of diabetes. Details: A meta-analysis of 7 large population studies has found that consuming dietary potassium 3300-3500 mg daily is associated with a 20% reduction in the risk of diabetes when compared with consumption below 1000 mg daily. Results were similar when studies that measured potassium intake with a dietary questionnaire were analyzed separately from those that measured intake based on urinary potassium excretion (110776). However, the validity of this finding is limited by the heterogeneity of the included studies. Furthermore, despite use of data from various databases, most studies included in the analysis were conducted by the same author.
• Impaired glucose tolerance (prediabetes). It is unclear if oral potassium improves glycemic control in prediabetes. Details: A small clinical study in Black patients with prediabetes shows that taking extended-release potassium (Klor-Con M10, Cardinal Health) 40 mEq daily as potassium chloride for 3 months does not improve glucose tolerance when compared with placebo. Although fasting glucose levels were slightly reduced in the potassium group when compared with placebo, both groups experienced a worsening of glucose intolerance, with no change in insulin levels or glycated hemoglobin (98533).
• Osteoporosis. Although there is interest in using oral potassium for osteoporosis, there is insufficient reliable information about the clinical effects of potassium for this condition.
• Physical performance. It is unclear if oral potassium improves physical performance in older adults. Details: Observational research in older adults has found that decreased dietary potassium intake and increased dietary sodium intake over 5 years is associated with worsened physical performance (105450).
• Systemic lupus erythematosus (SLE). It is unclear if oral potassium is beneficial in patients with SLE. Details: Observational research in patients with SLE has found that increased dietary potassium intake is not associated with improvements in disease activity scores or markers of cardiovascular disease, including lipid levels and blood pressure, when compared with low dietary potassium intake. However, higher potassium intake does seem to reduce the odds of having elevated levels of C-reactive protein, a marker of inflammation, in these patients (109397). More evidence is needed to rate potassium for these uses.

(Read more about POTASSIUM)

EFFECTIVE

• Ariboflavinosis. Oral riboflavin can treat and prevent low riboflavin levels.

POSSIBLY EFFECTIVE

• Hyperhomocysteinemia. Oral riboflavin reduces homocysteine levels in individuals with the MTHFR 677 TT genotype. It does not seem to provide benefit in individuals with other genotypes. Details: Population research has found that poor riboflavin status is associated with high homocysteine levels in individuals with the 677 TT genotype for the MTHFR enzyme (71386,71403,71409). Taking riboflavin 1.6 mg daily for 12 weeks reduces homocysteine levels by 22% to 40% in individuals with the 677 TT genotype of MTHFR when compared with pretreatment. However, riboflavin supplementation does not seem to reduce homocysteine levels in individuals with the 677 CC or CT genotypes (71443).
• Migraine headache. Oral riboflavin modestly reduces migraine attack frequency and severity in adults. The benefits of oral riboflavin in children are unclear. Details: A meta-analysis of 5 small clinical trials in adults with migraine shows that taking riboflavin 100-400 mg daily, alone or in combination with other natural ingredients, for three months modestly reduces migraine duration, frequency, and pain scores when compared with control (105480). These findings are limited by significant heterogeneity. Most clinical studies compared riboflavin 400 mg daily with placebo, no treatment, or an active control (1396,1397,1398,12387,105480). Limited evidence also suggests that taking riboflavin 400 mg daily might be no different for migraine prevention than certain conventional treatments such as bisoprolol 10 mg, metoprolol 200 mg, propranolol 80 mg, or valproate 500 mg (1396,105480). These findings are limited due to small study size and a lack of power to detect a difference between groups. Limited research has also evaluated riboflavin in children. A network meta-analysis of 3 small clinical trials in children with migraine shows that taking oral riboflavin 100-200 mg daily for 4-12 months does not significantly reduce incidence of migraine when compared with placebo. However, there was a non-significant trend towards reduced migraine frequency. Furthermore, conventional treatments such as propranolol, pregabalin, valproate, and topiramate were not shown to be significantly better than riboflavin for migraine prevention (105484). These findings are limited by small population sizes and insufficient power to detect differences between groups. Although riboflavin 100-200 mg has been used in prospective clinical studies, small observational studies have found some benefit in children taking riboflavin doses as low as 10-40 mg daily and as high as 400 mg daily for 3-4 months (105481,105485). Riboflavin has also been studied in combination with other ingredients, with research suggesting potential benefit. Specifically, riboflavin 400 mg has been combined with magnesium 600 mg and coenzyme Q10 150 mg daily (Dolovent; Linpharma Inc.) (92101), and also with magnesium 300 mg and feverfew 100 mg daily (12389).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there is interest in using oral riboflavin for acne, there is insufficient reliable information about the clinical effects of riboflavin for this purpose.
• Alzheimer disease. Although there is interest in using oral riboflavin for Alzheimer disease, there is insufficient reliable information about the clinical effects of riboflavin for this condition.
• Anxiety. It is unclear if oral riboflavin is beneficial for anxiety. Details: A large observational cohort study in adults suggests that a dietary riboflavin intake above 2.1 mg daily is associated with a 5% lower prevalence of anxiety when compared with a riboflavin intake less than 1.6 mg daily. Subgroup analysis suggests that this association is especially strong in males (111209).
• Cardiovascular disease (CVD). It is unclear if oral riboflavin can prevent mortality due to CVD. Details: Epidemiological research has found that dietary and supplemental riboflavin intake in the highest quartile, around 3.4 mg daily, is associated with a 47% lower risk of CVD mortality when compared with riboflavin intake in the lowest quartile, around 1 mg daily. The reduction in CVD mortality with riboflavin was enhanced by higher folate intake (110727). The validity of this finding is limited by the fact that dietary riboflavin intake was based on 2-day dietary recall.
• Carpal tunnel syndrome. Although there is interest in using oral riboflavin for carpal tunnel syndrome, there is insufficient reliable information about the clinical effects of riboflavin for this purpose.
• Cataracts. It is unclear if oral riboflavin is beneficial in patients with cataracts. Details: Observational research has found that high dietary intake of riboflavin is associated with a reduced risk of nuclear cataracts and age-related lens opacification (6378,14301). Furthermore, a clinical study in Chinese patients with nutrient deficiencies shows that taking a combination of riboflavin 3 mg plus niacin 40 mg daily also seems to reduce the risk of developing nuclear cataracts when compared with no supplementation (4885). It is unclear if the benefit is due to riboflavin, niacin, or the combination.
• Cervical cancer. It is unclear if oral riboflavin helps to prevent cervical cancer. Details: Epidemiological evidence has found that increased riboflavin intake from dietary and supplement sources, along with other B vitamins, is associated with a reduced risk of precancerous cervical lesions (11074).
• Cognitive function. Oral riboflavin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in healthy adults aged 40-65 years shows that taking a combination supplement containing riboflavin 70 mg, other group B vitamins, ginkgo leaf, and bacopa daily for 12 weeks does not improve measures of memory, attention, cognition, mood, or stress reactivity when compared with placebo (111334).
• Colorectal cancer. It is unclear if oral riboflavin reduces colorectal cancer risk. Details: Epidemiological evidence in a Chinese population suggests that increased dietary intake of riboflavin is associated with a reduced risk of developing colorectal cancer (105482).
• Depression. It is unclear if oral riboflavin is beneficial for depression. Details: A large cross-sectional study in middle-aged adults suggests that dietary riboflavin intake above 2.1 mg daily is associated with an 8% lower prevalence of depression when compared with a riboflavin intake less than 1.6 mg daily. Subgroup analysis suggests that this association is especially strong in males (111209).
• Diabetes. It is unclear if oral riboflavin reduces the risk of developing gestational diabetes. Details: A large prospective cohort study in pregnant adults shows that supplementation with riboflavin at doses over 2.5 mg daily during the first trimester and 2.1 mg daily in the second trimester is associated with a lower risk of developing gestational diabetes when compared with riboflavin doses under 1.1 mg daily. However, this effect was not found for dietary intake of riboflavin, only supplementation. Additionally, the participants were mostly Han Chinese adults, limiting the generalizability of the findings to other populations (111680).
• Diabetic neuropathy. Intravenous and oral riboflavin have only been evaluated in combination with other ingredients; riboflavin's effect when used alone is unclear. Details: Clinical research in patients with type 2 diabetes shows that intravenous administration of a specific combination product containing succinic acid, inosine, nicotinamide, and riboflavin (Cytoflavin, Polysan) daily for 10 days followed by an oral formulation of the same product, taken daily for 76 days, reduces symptoms of diabetic neuropathy including paresthesia, numbness, and burning when compared with placebo (110503). It is unclear if these findings are due to riboflavin, other ingredients, or the combination.
• Esophageal cancer. It is unclear if oral riboflavin reduces esophageal cancer risk. Details: Population research in Iranian patients has found that low riboflavin status is associated with a two-fold increase in the risk of esophageal cancer (71439). However, not all evidence agrees. Preliminary clinical studies in Chinese individuals with esophageal dysplasia shows that taking riboflavin, alone or in combination with calcium or niacin, for 3-5 years does not seem to reduce the risk of esophageal cancer in patients when compared with baseline or control (4679,63576,71488). Taking riboflavin 200 mg weekly, in combination with retinol 15 mg and zinc 50 mg, also does not seem to be beneficial in this patient population (71501). It is unclear if these findings are generalizable to geographic locations other than China and Iran.
• Gastric cancer. It is unclear if oral riboflavin reduces colorectal cancer risk. Details: Low quality clinical research in a Chinese population shows that taking riboflavin in combination with niacin does not reduce the risk of gastric cancer when compared with control (4679).
• Hypertension. There is limited evidence on the oral use of riboflavin for reducing blood pressure in patients with the MTHFR 677 TT genotype. Details: A 677 C to T polymorphism on the MTHFR gene has been associated with hypertension. In patients with a confirmed MTHFR 677 TT genotype and premature cardiovascular disease, preliminary clinical research suggests that taking riboflavin 1.6 mg daily for 16 weeks reduces systolic blood pressure (SBP) by 9 mmHg and diastolic blood pressure (DBP) by 6 mmHg when compared with placebo. This decrease in blood pressure is larger than that reported in other trials, which may be due to the fact that only patients with the 677 TT genotype were included. These patients seem to respond to riboflavin therapy more so than patients with 677 CC or 677 CT genotype (92102). Additional clinical research in patients with the 677 TT genotype but without cardiovascular disease shows that taking riboflavin 1.6 mg daily for 16 weeks reduces SBP by 5.6 mmHg but does not reduce DBP (92103). There is also interest in using dietary riboflavin for reducing the onset of hypertension. Some epidemiological evidence in a Chinese population has found that increased dietary intake of riboflavin is associated with a reduced risk of developing hypertension (105483).
• Liver cancer. Oral riboflavin has only been evaluated in combination with niacin; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese individuals older than 55 years shows that taking riboflavin in combination with niacin does not seem to prevent liver cancer mortality when compared with control. However, there was a reduced risk of liver cancer mortality in people aged less than 55 years when compared with control (63470).
• Lung cancer. Oral riboflavin has only been evaluated in combination with niacin; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese individuals shows that taking riboflavin in combination with niacin does not appear to reduce the risk of lung cancer when compared with control (34539).
• Malaria. Oral riboflavin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children ages 5-14 years living in Gambia and at high risk for malaria exposure suggests that taking riboflavin, in combination with iron, thiamine, and vitamin C, for 3 months does not reduce the frequency or severity of malaria infections when compared with placebo (56730).
• Malnutrition. There is limited evidence on the oral use of riboflavin with other ingredients in children at risk for kwashiorkor. Details: A clinical study in Malawian children at risk for kwashiorkor, a severe form of malnutrition, suggests that taking riboflavin, vitamin E, selenium, and N-acetyl cysteine at a dose of three times the recommended dietary allowance does not prevent kwashiorkor, reduce edema, increase physical growth, or reduce infection when compared with placebo (71433).
• Mitochondrial myopathies. Although there is interest in using oral riboflavin for mitochondrial myopathies, there is insufficient reliable information about the clinical effects of riboflavin for this condition.
• Multiple sclerosis (MS). It is unclear if oral riboflavin slows the progression of MS-related disability. Details: A small clinical study in patients with relapsing-remitting MS or secondary progressive MS who are undergoing treatment with disease-modifying therapies suggests that taking oral riboflavin 10 mg daily for six months is no more effective for improving disability than placebo (91752). The validity of this finding is limited by the small study sample size.
• Oral leukoplakia. It is unclear if oral riboflavin prevents or slows progression of oral leukoplakia. Details: Population research in people living in Uzbekistan suggests that low blood levels of riboflavin are associated with an increased prevalence of oral leukoplakia (71502). However, clinical evidence in patients with a high occurrence of oral and esophageal cancer who are living in Uzbekistan suggests that taking riboflavin 80 mg weekly for 20 months does not improve the prevalence or progression of oral leukoplakia when compared to baseline (71565). The validity of this finding is limited by the lack of a placebo group and unusual once weekly dosing. Furthermore, it is unclear if these results are generalizable to other geographic locations.
• Pre-eclampsia. Although there is interest in using oral riboflavin for pre-eclampsia, there is insufficient reliable information about the clinical effects of riboflavin for this purpose.
• Pregnancy-related iron deficiency. It is unclear if oral riboflavin is beneficial in patients with iron deficiency due to pregnancy. Details: Preliminary clinical research in pregnant patients in China suggests that adding riboflavin 1 mg daily to supplemental iron and folic acid does not improve iron status when compared with taking iron and folic acid alone (71480).
• Sickle cell disease. It is unclear if oral riboflavin is beneficial in patients with sickle cell disease. Details: One small clinical study in patients with sickle cell disease suggests that taking riboflavin 5 mg twice daily for 8 weeks increases serum iron and transferrin saturation when compared to baseline; however, riboflavin does not seem to improve serum ferritin or circulating hemoglobin levels (71566).
• Stroke. Oral riboflavin has only been evaluated in combination with niacin; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese individuals with poor nutritional status who are at risk for stroke suggests that taking riboflavin 5.2 mg daily in combination with niacin 40 mg daily does not reduce the risk of stroke-related mortality (2673). More evidence is needed to rate riboflavin for these uses.

(Read more about RIBOFLAVIN)

LIKELY EFFECTIVE

• Selenium deficiency. Oral selenium is effective for the treatment and prevention of selenium deficiency. Details: Selenium supplementation is effective for reversing symptoms of selenium deficiency, as well as for preventing the development of selenium deficiency (4844,90357).

POSSIBLY EFFECTIVE

• Autoimmune thyroiditis. Oral selenium seems to improve autoimmune thyroiditis in adults, but the evidence of benefit in children is conflicting. Details: A meta-analysis of mostly small, low-quality clinical and observational studies in children and adults with Hashimoto thyroiditis shows that taking selenium 83 mcg, selenomethionine 50 mcg or 200 mcg, or selenium 83 mcg with myoinositol 600 mg daily for 3 to 6 months reduces thyroid peroxidase antibody (TPOAb) levels and thyroglobulin antibody (TgAb) levels after 6 months of treatment when compared with baseline or placebo. However, there was no change in thyroid antibody levels at 3 months, suggesting a longer duration of 6 months is needed to sufficiently reduce serum antibody levels. Additionally, subgroup analysis suggests that patients with higher baseline thyroid antibody levels might benefit more from selenium supplementation compared to those with lower baseline thyroid antibody levels (113645). The validity of these effects is limited by high heterogeneity between baseline thyroid antibody levels amongst the included studies. Additionally, clinical research in adults with thyroiditis shows that taking selenium up to 200 mcg daily in combination with levothyroxine reduces TPOAbs by about 6% to 30% more than placebo after 3-12 months of treatment (9797,17510,17511,17512,17513,17515,17516,97943,104424). Selenium also seems to improve measures of quality of life such as feelings of well-being and mood (17515). Doses under 200 mcg daily might not be as effective (17512); selenomethionine might be more effective than sodium selenite (97943). Some research shows that selenium might be more effective in patients with more severe disease activity and less effective in patients with only moderate disease activity (9797,17513,17515). Also, selenium might not reduce TPOAbs in patients newly diagnosed with thyroiditis not receiving concurrent levothyroxine (97943). There is no reliable evidence about the effect of selenium on thyroid function or thyroid morphology. Despite positive findings in adults, most clinical research in children suggests that taking selenium 50-200 mcg daily for 3-12 months does not significantly improve TPOAb, TgAb, or thyroid echogenicity (17514,90362).
• Kashin-Beck disease. Selenium seems to help prevent Kashin-Beck disease, but does not improve symptoms in patients with existing disease. Details: A meta-analysis of prospective studies conducted in China shows that adding salt enriched with selenium to the diet of healthy children for up to 4 years reduces the odds of developing Kashin-Beck disease by 84% when compared with the use of iodine salt. Additionally, in children with Kashin-Beck disease, adding salt enriched with selenium to the diet might help heal metaphyseal lesions (97945). However, selenium does not seem to improve symptoms in those with existing disease. A clinical trial in children with Kashin-Beck disease shows that selenium supplementation does not improve joint pain or mobility when compared with placebo (55941).
• Pre-eclampsia. Oral selenium might reduce the risk of pre-eclampsia in pregnant patients. Details: A meta-analysis of three low-quality clinical trials in pregnant patients shows that taking selenium 60-100 mcg daily for up to 6 months reduces the risk of pre-eclampsia by 72% when compared with placebo. Additionally, a meta-analysis of population research has found that the risk of pre-eclampsia is higher in pregnant patients with low selenium levels. Selenium levels were about 6.5 mcg/L lower in those who developed pre-eclampsia compared with those who did not (97946).

POSSIBLY INEFFECTIVE

• Asthma. Oral selenium does not seem to improve asthma symptoms. Details: Epidemiological research has found that plasma selenium concentration is not associated with asthma (74422). Also, clinical research in patients with asthma shows that taking selenium 100 mcg daily for 14-24 weeks does not improve symptoms, lung function, use of rescue inhalers, or quality of life when compared with placebo (74490,74387).
• Atopic dermatitis (eczema). Oral selenium-enriched yeast does not seem to improve eczema symptoms. Details: A small clinical study in patients with eczema shows that taking selenium-enriched yeast 600 mcg daily for 12 weeks, either alone or in combination with vitamin E 600 IU daily, does not improve symptom severity when compared with placebo (74456).
• Cardiovascular disease (CVD). Most research shows that oral selenium does not reduce the risk of CVD. Details: Meta-analyses of clinical trials in patients with and without risk factors for CVD show that taking selenium alone or with other supplements for up to 8 years does not reduce the risk of CVD mortality or fatal and non-fatal CVD events (90360,97078). When reported, patients in these studies all had adequate plasma selenium levels at baseline (90360).
• Colorectal cancer. Oral selenium does not seem to prevent cancer of the colon and rectum. Details: Epidemiological research has found no association between serum concentrations of selenium and the risk of developing colorectal cancer (74321,97085). Also, meta-analyses of clinical research, as well as individual clinical trials, show that taking selenium 100-200 mcg daily, alone or in combination with other vitamins and minerals, does not reduce the risk of colorectal cancer when compared with control (16707,34676,90361,97092).
• Dyslipidemia. Most research shows that oral selenium supplementation does not improve cholesterol levels. Details: A meta-analysis of 11 clinical studies in adults with dyslipidemia shows that taking selenium 50-300 mcg daily for 8-24 weeks does not increase high-density lipoprotein (HDL) cholesterol levels or decrease total or low-density lipoprotein (LDL) cholesterol levels when compared with placebo. Taking selenium might modestly improve triglyceride levels, but this improvement is unlikely to be considered clinically significant (99662). Another meta-analysis of 21 mostly small, low-quality clinical studies, some of which were included in the prior meta-analysis, shows that taking various forms of selenium may modestly decrease total cholesterol levels, but does not improve triglycerides, LDL, or HDL cholesterol when compared with placebo (110595). However, the validity of the findings from this meta-analysis is limited by the heterogeneity of the included studies, which assessed various selenium dosing regimens and enrolled healthy patients or those with various cardiovascular and non-cardiovascular conditions.
• Low birth weight. Oral or intravenous selenium supplementation does not improve outcomes in low birth weight infants. Details: Low selenium levels have been documented in low birth weight infants. However, selenium supplementation, orally or intravenously, does not appear to improve most outcomes in low birth weight infants. Clinical research shows that administering selenium, either as 7-10 mcg/kg daily parenterally or 5 mcg/kg daily orally, does not improve oxygen dependency or reduce the risk of death in low birth weight infants when compared with placebo. However, supplementation decreases the incidence of sepsis by up to 33% (74288,97083).
• Lung cancer. Oral selenium does not reduce lung cancer risk in most patients. Details: While a large cohort study suggests that increased dietary intake of selenium is associated with a lower risk of lung cancer, supplemental selenium does not appear to have the same effect. Additionally, a meta-analysis of three large clinical trials of over 20,000 patients, including patients with resected stage I non-small-cell lung cancer, shows that taking selenium 200-400 mcg daily for up to 5 years does not reduce the risk of lung cancer when compared with control (92912,97092). A secondary analysis of one of these studies found that selenium supplementation might reduce lung cancer risk in people with selenium levels below 105 ng/mL (9798). Also, a large study in healthy Chinese patients shows no benefit of using selenium in combination with other nutrients for over 5 years when compared with control (34539).
• Nonmelanoma skin cancer. Oral selenium does not reduce the risk of nonmelanoma skin cancer and has been linked to increased risk in some patients. Details: Epidemiological research has found that higher selenium intake is not associated with a reduced risk of nonmelanoma skin cancer (97085). Furthermore, clinical research shows that taking selenium orally 200 mcg daily does not reduce the risk of basal cell carcinoma when compared with control (2664,10687). In addition, some evidence shows that daily selenium supplementation might increase the risk of squamous cell carcinoma and total non-melanoma skin cancer (10687).
• Prostate cancer. Oral selenium does not seem to reduce prostate cancer risk. Details: Population studies have found that higher serum or toenail selenium levels are associated with a decreased risk of prostate cancer (8734,8735,8736,92911,10263). However, clinical research does not support this finding. A meta-analysis of 5 large clinical trials of over 20,000 patients shows that selenium 200-400 mcg daily for up to 5 years does not reduce the risk of prostate cancer when compared with control (97092). A 7-14 year follow-up study of one of these trials shows there was still no reduction of prostate cancer risk (17688). Selenium has also shown no benefit when used in combination with other supplements. In a large-scale clinical study (SU.VI.MAX), taking selenium 100 mcg in combination with vitamin C, vitamin E, beta-carotene, and zinc did not reduce prostate cancer risk (14135). In 2009, the US Food and Drug Administration (FDA) approved a qualified health claim regarding selenium and prostate cancer risk, stating that it is highly unlikely that selenium supplements reduce the risk of prostate cancer (102373).
• Psoriasis. Oral selenium does not seem to reduce psoriasis severity. Details: Clinical research shows that taking selenium-enriched yeast 600 mcg daily for 12 weeks, either alone or in combination with vitamin E 600 IU daily, does not reduce the severity of psoriasis when compared with placebo (74460).
• Sepsis. Intravenous selenium does not appear to improve outcomes in septic adults. Details: Earlier meta-analyses of clinical trials in septic adults showed that parenteral administration of selenium, along with routine nutritional interventions, reduces the risk of mortality by 11% to 27% when compared with placebo (90347,92907,92910). However, a more recent meta-analysis, which includes a large, multi-center study of over 1000 cases, shows that parenteral selenium does not reduce mortality in septic adults at 28, 90, or 180 days when compared with placebo (99658). Enteral selenium with other nutrients has been studied for sepsis in children. Clinical research in children shows that taking enteral selenium 40-400 mcg daily with zinc, glutamine, and IV metoclopramide is no more effective than whey protein for reducing time to first episode of nosocomial infection or sepsis in the intensive care unit (ICU). However, the selenium combination treatment might reduce the risk for sepsis in immunocompromised pediatric patients (86095).

LIKELY INEFFECTIVE

• Bladder cancer. Despite promising initial research, oral selenium does not seem to prevent the development, recurrence, or progression of bladder cancer. Details: In 2009, the US Food and Drug Administration (FDA) approved a qualified health claim regarding selenium and bladder cancer risk based on two small studies. However, the FDA determined that it is highly uncertain that selenium supplements reduce the risk of bladder cancer (102373). Since then, most available research has not confirmed an association between selenium and bladder cancer risk. Epidemiological and clinical research suggests that selenium supplementation is not associated with a reduced risk of bladder cancer and does not prevent recurrence, slow progression, or improve overall survival in patients with bladder cancer (97085). One moderate-sized clinical study shows that taking selenium 200 mcg daily with or without vitamin E 200-400 IU daily for 7 years does not prevent bladder cancer in older males (90352). Another small clinical study shows that taking selenium yeast 200 mcg daily for 3 years does not prevent the recurrence of bladder cancer when compared with placebo in patients that had undergone a transurethral resection for non-invasive bladder cancer (97087). These findings are supported by another moderate-sized clinical study in adults with non-invasive bladder cancer which shows that taking selenium 200 mcg with or without vitamin E 200 IU daily for a median of 1.5 years does not prevent recurrence, slow bladder cancer progression, or improve overall survival when compared with placebo over a median follow-up period of 5.5 years (114116).
• Diabetes. Increased intake of selenium, either in the diet or as a supplement, is associated with an increased risk for developing type 2 diabetes. It is unclear if oral selenium is beneficial in patients with type 2 diabetes. Details: Observational research suggests that high serum selenium levels, high dietary selenium intake, and selenium supplementation are each linked to an increased risk of developing diabetes (97091,99661). Consuming more than the recommended dietary allowance (RDA) of selenium daily is associated with an increased risk of developing diabetes when compared with consuming less than the RDA (99661). However, the effect of short-term selenium supplementation in patients with diabetes is unclear. Two meta-analyses of clinical studies in adults with various health conditions show that taking supplemental selenium as selenium yeast, sodium selenite, or selenomethionine in doses of 100-960 mcg daily for 4 to 96 weeks reduces serum and fasting insulin levels and increases measures of insulin sensitivity but does not lower fasting blood glucose or glycated hemoglobin (HbA1c) when compared with placebo. Additionally, selenium supplementation does not reduce total or low-density lipoprotein (LDL) cholesterol or triglycerides but may improve high-density lipoprotein (HDL) cholesterol (110593). However, the validity of the findings from the meta-analyses is limited by the heterogeneity of the included studies, which enrolled healthy adults and patients with diabetes, gestational diabetes, cardiovascular disease, heart failure, obesity, polycystic ovary syndrome (PCOS), cancer, and Alzheimer disease.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral selenium reduces the risk of cognitive decline in older adults. Details: A cross-sectional study in elderly Americans has found that lower blood levels of selenium are associated with a greater risk of poor cognitive scores when compared with higher levels (104426).
• Alcohol-related liver disease. Although there is interest in using oral selenium for alcohol-related liver disease, there is insufficient reliable information about the clinical effects of selenium for this condition.
• Allergic rhinitis (hay fever). Although there is interest in using oral selenium for allergic rhinitis, there is insufficient reliable information about the clinical effects of selenium for this condition.
• Alzheimer disease. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with Alzheimer disease shows that taking selenium 200 mcg with a probiotic daily for 12 weeks improves cognitive function as measured by the Mini-Mental State Examination (MMSE) when compared with placebo. However, when selenium 200 mcg was taken alone, no improvement in cognitive function over placebo was found, so it is unclear whether the improvements in cognitive function are due to the probiotics or the combination of ingredients (113659). Another very small clinical study in adults with mild-to-moderate Alzheimer disease shows that taking supranutritional selenium 30 mg daily for 12 weeks does not change cognitive measures, cerebrospinal fluid biomarkers, or neuroimaging biomarkers of Alzheimer disease progression when compared with placebo or nutritional selenium doses. However, the control group showed worsened diffusivity imaging markers indicative of deterioration of axonal structure integrity, while no such decline was noted in supranutritional selenium neuroimaging (113660).
• Androgenic alopecia. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in adults with androgenic alopecia or telogen effluvium shows that taking a combination product containing selenium, hydrolyzed collagen, taurine, cysteine, methionine, and iron (GFM Oral, Cantabria Labs) daily for 12 weeks daily along with conventional therapy, consisting primarily of finasteride or minoxidil, improves hair loss when compared with conventional therapy alone (111636). It is unclear if this effect is due to selenium, other ingredients, or the combination.
• Arsenic poisoning. It is unclear if oral selenized yeast is beneficial for patients that were exposed to high levels of arsenic in the environment. Details: A small clinical study in Chinese people environmentally exposed to high concentrations of arsenic shows that taking selenized yeast providing 100-200 mcg of selenium daily for 14 months decreases the concentration of arsenic and symptoms of toxicity when compared with placebo (7831).
• Benign prostatic hyperplasia (BPH). Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in men with BPH shows that taking selenium 240 mcg plus silymarin 570 mg daily for 6 months reduces lower urinary tract symptoms when compared with placebo (88155). Another clinical study in men with BPH shows that taking tamsulosin 0.4 mg plus a specific product containing selenium, saw palmetto, and lycopene (Profluss, Ayanda AS) daily for one year improves lower urinary tract symptoms and urodynamic parameters when compared with tamsulosin-alone (90354). It is unclear if these effects are due to selenium, other ingredients, or the combinations.
• Burns. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Small clinical studies in patients with burns on 46% of their body surface suggest that taking a combination of copper 2.5-3.1 mg, selenium 315-380 mcg, and zinc 26.2-31.4 mg daily reduces the incidence of hospital-acquired pneumonia, but does not seem to improve wound healing, hospital stay, or mortality, when compared with placebo (6520,74382). Another very small clinical study in burn patients suggests that taking copper 4.5 mg, selenium 190 mcg, and zinc 40 mg daily reduces the duration of hospitalization, but does not have an effect on recovery and wound treatment requirements, when compared with standard dietary doses of these nutrients (74485).
• Cancer. Selenium does not seem to reduce the risk of cancer in most people, but it might be beneficial in those with low selenium levels and in men. Details: Meta-analyses of clinical research and several clinical studies show that selenium supplementation does not reduce the incidence of cancer or cancer-related mortality when compared with control (14109,34538,74414,97078,97092). In clinical studies, selenium 100-400 mcg taken daily for 2-7.5 years with or without additional antioxidants did not reduce overall cancer risk (14109,34538,74414). However, most evidence did not assess baseline selenium levels. Other evidence suggests that selenium may have a benefit in men and in people with lower selenium levels. Epidemiological research has found that selenium intake at the recommended daily allowance (RDA) of 55 mcg or higher is associated with decreased cancer incidence and cancer mortality, especially in men (97085,103164). However, this research suggests that cancer risk was also influenced by age, body mass index, and smoking status (103164). Some clinical research also suggests that taking selenium might decrease the risk of cancer, when only men are considered (14109). An older meta-analysis of clinical research suggests that selenium was particularly beneficial in patients with lower baseline levels of selenium and in patients at high risk for cancer (90350). In 2003, the US Food and Drug Administration (FDA) approved a qualified health claim stating that consumption of selenium may produce anticarcinogenic effects and reduce the risk for certain forms of cancer. However, the FDA has determined that the evidence is limited and inconclusive (102374).
• Cataracts. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: An ancillary clinical study shows that taking selenium 200 mcg daily with or without vitamin E 400 IU daily for around 5.6 years does not reduce the risk of age-related cataracts in men when compared with placebo (92902).
• Cervical dysplasia. It is unclear if oral selenized yeast is beneficial for patients with cervical dysplasia of mild severity. Details: A small clinical study in patients with cervical intraepithelial neoplasia grade 1 (CIN1) shows that taking yeast containing selenium 200 mcg daily for 6 months resulted in regression of CIN1 in 88% of participants, compared with regression in only 55% of participants taking placebo (97944).
• Chemotherapy-induced nephrotoxicity. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in cancer patients shows that drinking a beverage containing vitamin C, vitamin E, and selenium does not prevent cisplatin-induced nephrotoxicity when compared with a placebo beverage (74340). However, poor compliance to treatment may limit the validity of these findings.
• Chronic fatigue syndrome (CFS). Although there is interest in using oral selenium for CFS, there is insufficient reliable information about the clinical effects of selenium for this condition.
• Cirrhosis. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with primary biliary cirrhosis shows that taking a combination of selenium, vitamin A, vitamin C, vitamin E, methionine, and coenzyme Q10 for 12 weeks does not improve fatigue or any other disease-related symptoms when compared with placebo (34494).
• Cisplatin-associated ototoxicity. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in cancer patients shows that drinking a beverage containing vitamin C, vitamin E, and selenium does not prevent cisplatin-associated hearing loss when compared with placebo beverage (74340). However, poor compliance to treatment may limit the validity of these findings.
• Colorectal adenoma. It is unclear if oral selenium prevents recurrence of adenomas in the colon and rectum. Details: A large clinical study in patients with a history of colorectal adenomas shows that taking a specific selenium supplement (SelenoExcell High Selenium Yeast, Cypress Systems) 200 mcg daily for about 33 months does not reduce adenoma recurrence when compared with placebo. However, in a sub-group of patients with advanced adenomas at baseline, selenium seems to reduce risk of recurrence by 18% when compared with placebo (97091). Some research also shows that taking selenium in combination with zinc, and vitamins A, C, and E reduces adenoma recurrence when compared with placebo (92903). It is not clear any benefit is due to selenium, other nutrients, or the combination.
• Congestive heart failure (CHF). Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study in elderly patients with heart failure living in Sweden shows that taking a specific selenium supplement (SelenoPrecise, Pharma Nord) 200 mcg plus a specific coenzyme Q10 supplement (Bio-Quinon, Pharma Nord) 200 mg daily for about 4 years reduces the risk of cardiovascular mortality by about 55% when compared with placebo (92904). The risk reduction seems to be most pronounced in patients with lower selenium levels (97906). Furthermore, at 10- and 12-year follow-ups, cardiovascular mortality in the treatment group continued to be 49% and 41% lower, respectively, when compared with placebo (96546,97466). It is unclear if the benefit can be attributed to selenium, coenzyme Q10, or the combination.
• Coronary artery bypass graft (CABG) surgery. It is unclear if oral selenized yeast is beneficial for patients undergoing CABG surgery. Details: A small clinical study in patients undergoing CABG surgery shows that taking selenium 200 mcg daily as selenium yeast for 4 weeks improves glycemic control, lipid levels, and markers of inflammation when compared with placebo (103163). It is not known whether this influences the outcome or complications of CABG surgery.
• Critical illness (trauma). Evidence on the use of intravenous selenium in critically ill patients is conflicting. Details: The most recent meta-analysis of 24 clinical trials in critically ill patients shows that intravenous selenium does not improve survival over 6 months, shorten hospital stay, or reduce intensive care unit (ICU) stay, infectious complications, development of acute kidney failure, or duration of mechanical ventilation when compared with control. Also, length of ICU stay was increased by about 4.5-fold in patients receiving selenium in doses of more than 1000 mcg daily (109086). These findings are similar to those of a meta-analysis of 21 randomized controlled trials in critically ill patients from 2016 which shows that intravenous selenium given alone or with other nutrients does not improve mortality, duration of hospital stay, or kidney function when compared with control (97090). However, another recent meta-analysis of 19 clinical trials in critically ill patients shows that intravenous selenium reduces total mortality by 14% and shortens hospital stay by about 2 days when compared with control, without affecting ICU stay, duration of mechanical ventilation, or mortality over 28 days (101345). The reasons for these discrepancies are not clear and do not seem to be completely explained by differences in doses or durations of selenium (109086). Some reasons for the discrepancies might include differing analytic methods used in meta-analyses, as well as variations in forms of selenium, concomitant treatments, and specific patient populations. One sub-analysis shows that, when limited to randomized controlled trials examining the effect of selenium supplementation in patients sustaining traumatic injury, the odds of mortality was reduced by about 26% and duration of ICU and hospital stay were modestly reduced. There was no effect on infectious complications (109090).
• Dementia. It is unclear if oral selenium prevents dementia or reduces symptoms. Details: Observational research has found that taking selenium 200 mcg daily for 4 years does not decrease the incidence of dementia in men 60 years or older (93570). However, the follow-up period may not have been long enough to reliably detect the effect of selenium on the development of dementia. Also, the screening method used to detect new cases of dementia may have failed to identify individuals presenting with only the initial symptomatic stages of the disease (93570,93571).
• Depression. It is unclear if oral selenium is beneficial for the treatment of prevention of depression. Details: A meta-analysis of observational research has found no difference in serum levels of selenium between patients with or without depression. In addition, serum levels of selenium do not correlate with depression scores (109091). A meta-analysis of clinical research shows that selenium supplementation, usually 100-200 mcg daily, modestly reduces symptoms of depression; however, at least one of the three studies included in this meta-analysis investigated the effects of selenium in patients with postpartum depression, specifically (109091). These meta-analyses are limited by the quality of included research and the small number of available studies.
• Diabetic nephropathy. It is unclear if oral selenium alleviates diabetic nephropathy symptoms. Details: A small clinical study in patients with diabetic nephropathy shows that taking selenium (Nature Made) 200 mcg daily for 12 weeks does not improve kidney markers such as blood urea nitrogen or serum creatinine when compared with placebo (97084).
• Dilated cardiomyopathy. There is limited evidence on the oral use of selenium in patients with Keshan disease and peripartum cardiomyopathy. Details: Observational research in patients with a specific type of dilated cardiomyopathy called Keshan disease and congestive heart failure has found that selenium supplementation is associated with a 61% decreased risk of cardiac death when compared with no supplementation (101346). A small clinical study in patients with peripartum cardiomyopathy and selenium deficiency shows that taking selenium 200 mcg daily for 3 months does not seem to improve heart failure symptoms or left ventricle systolic function, or prevent death, when compared with no treatment (104420).
• Esophageal cancer. Limited research suggests that oral selenium does not reduce esophageal cancer risk. Details: Low quality clinical research suggests that taking selenium supplements alone or with other vitamins does not decrease the risk of esophageal cancer when compared with control (4679,12185).
• Gastric cancer. Oral selenium has only been evaluated in combination with other ingredients and in a specific patient population; its effect when used alone and in other populations is unclear. Details: Population research in Chinese patients has found that high levels of selenium are associated with lower risk of gastric cancer and cancer mortality (97948). However, clinical research does not agree. A large clinical study in patients residing in China shows that taking selenium 37.5 mcg in combination with vitamin C 250 mg and vitamin E 100 IU twice daily for about 7.3 years does not reduce the risk of developing gastric cancer or precancerous gastric lesions when compared with placebo. This combination treatment was not associated with reduced gastric cancer incidence or mortality at the 14-year follow-up of this study (14447,51470). Another clinical study in healthy Chinese adults also shows that taking a combination of selenium 50 mcg, vitamin E 30 mg, and beta-carotene 15 mg daily for 5.2 years does not reduce the risk of gastric cancer when compared with control (4679). It is unclear if these findings are generalizable to populations in geographic locations other than China.
• Graves' ophthalmopathy. It is unclear if oral selenium is beneficial for Graves' ophthalmopathy. Details: A small clinical trial in adults with Graves' ophthalmopathy shows that taking selenium 100 mcg twice daily for 6 months is modestly beneficial for reducing disease activity, based on signs and symptoms including pain, swelling, and redness, when compared with placebo (109085).
• Hepatitis C. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with hepatitis C shows that taking a combination of selenium 200 mcg, vitamin C 500 mcg, and vitamin E 945 IU daily for 6 months does not have an effect on levels of alanine aminotransferase or viral load when compared with placebo (74377).
• HIV/AIDS. It is unclear if oral selenium improves outcomes in patients with HIV. Details: Clinical trials in HIV-positive men and women, most receiving anti-retroviral therapy (ART), shows that taking selenium 200 mcg daily for up to 2 years can reduce HIV-1 viral load, increase CD4 cell counts, and lower the risk of hospitalizations when compared with placebo (15266,74314). However, not all research agrees. Two small clinical trials in HIV-positive patients taking ART shows that taking selenium 100-200 mcg daily for 6-12 months does not reduce the risk for opportunistic infections and does not increase CD4 counts when compared with control (7830,104417). Furthermore, selenium does not seem to benefit patients that are not receiving conventional ART. A large clinical study in HIV-infected pregnant patients in Tanzania with poor access to ART shows that taking selenium 200 mcg daily with prenatal vitamins until 6 months after delivery, does not improve progression of HIV nor pregnancy outcomes when compared with no selenium supplementation (74419). Another large clinical study in HIV-infected and ART-naïve patients in Botswana shows that taking selenium 200 mcg daily for 24 months does not slow HIV progression when compared with placebo (92905).
• Hypertension. It is unclear if oral selenium improves blood pressure. Some evidence suggests selenium supplementation may slightly increase systolic blood pressure. Details: A meta-analysis of 5 small clinical studies in adults with various health conditions shows that taking selenium or selenium yeast 100-200 mcg/day for 6-12 weeks may increase systolic blood pressure by about 2 mmHg but does not impact diastolic blood pressure when compared with placebo (110595). However, the validity of the findings from this meta-analysis is limited by the heterogeneity of the included studies, which enrolled patients with preeclampsia, gestational diabetes, obesity, or heart failure. Additionally, all studies were conducted in Iran; it is unclear if these findings are generalizable to populations in other geographic locations.
• Hyperthyroidism. It is unclear if oral selenium alleviates symptoms in patients with Graves' disease. Details: A small clinical study in patients with Graves' hyperthyroidism shows that taking sodium selenite 300 mcg daily in addition to treatment with methimazole for 24 weeks does not affect symptoms or recurrence rates when compared with placebo plus methimazole (97089). Oral selenium has also been studied in combination with other supplements. A small preliminary clinical trial in patients with newly diagnosed Graves' disease and low levels of selenium and vitamin D shows that taking selenium 100 mcg daily for 180 days along with vitamin D as cholecalciferol 7000 IU weekly for 270 days, in addition to methimazole, modestly reduces levels of serum free thyroxine and improves quality of life when compared with methimazole alone. However, taking selenium and vitamin D did not affect levels of free triiodothyronine or positive thyroid stimulating hormone (TSH) receptor antibody (109049).
• Hypothyroidism. It is unclear if oral selenium improves thyroid hormone balance in elderly individuals, pregnant patients, or patients with subclinical hypothyroidism. In patients with iodine deficiency, selenium supplementation may be harmful. Details: Low selenium levels or selenium deficiency seems to reduce conversion of thyroxine (T4) to triiodothyronine (T3). However, clinical research in healthy elderly patients is conflicting. Although one study shows that taking selenium 100 mcg daily for 3 months increases conversion of T4 to T3 when compared with placebo (17508), a larger study shows that taking selenium 100-300 mcg daily for 6 months does not impact conversion of T4 to T3 when compared with placebo (17509). Additionally, taking selenium can worsen hypothyroidism in people with iodine deficiency. People who are iodine- and selenium-deficient should not receive selenium supplements without concomitant iodine. In these individuals, selenium increases conversion of T4 to T3, but the thyroid gland lacks iodine to synthesize more T4 (1664,14563,14564,14565,17508). Selenium does not have a significant effect on thyroid function when iodine intake is adequate (1664,4844). In pregnant patients with hypothyroidism, clinical research shows that taking selenium does not reduce complications such as pre-eclampsia or preterm birth. However, selenium might improve postpartum thyroid function and decrease the risk of postpartum thyroiditis (17507). Also, taking selenium 200 mcg daily during pregnancy seems to reduce the risk of developing postpartum thyroid dysfunction and permanent hypothyroidism by 41% and 42%, respectively, when compared with placebo in euthyroid pregnant patients who are positive for thyroid peroxidase antibodies (74391). Selenium supplementation has also been studied for subclinical hypothyroidism. Clinical research in females aged 18 to 50 years with or at risk for subclinical hypothyroidism in Slovakia shows that taking selenium 83 mcg daily and myo-inositol 600 mg daily for 6 months modestly reduces thyroid stimulating hormone (TSH) and thyroid auto-antibody titers when compared with baseline. Selenium and myo-inositol supplementation also reduced patient-reported hypothyroid symptoms including fatigue, menstrual cycle irregularity, and intolerance to heat or cold (110591). The interpretation of these results is limited by the lack of a control group. In addition, it is unclear if these effects are due to selenium, myo-inositol, or the combination.
• Influenza. Although there is interest in using oral selenium for influenza, there is insufficient reliable information about the clinical effects of selenium for this condition.
• Kidney failure. It is unclear if oral selenium is beneficial for improving lipid parameters in patients on hemodialysis. Details: Selenium levels may be low in patients undergoing chronic hemodialysis, and supplementation might be needed (1805,11053). However, clinical research in patients on hemodialysis shows that taking selenium daily for 3 months does not improve the lipid profile when compared with taking placebo (109095).
• Lichen planus. It is unclear if topical or oral selenium alleviates oral lichen planus symptoms. Details: A small clinical study in patients with oral lichen planus shows that applying a selenium hydrogel (selenomethionine 14 mcg/gram) twice daily for 6 weeks seems to significantly reduce pain at a 12 week follow-up, but not immediately after use, when compared with applying topical corticosteroids and antifungal agents 2-4 times daily. Taking oral selenium 200 mcg twice daily for 6 weeks seems to be no different than the topical corticosteroids and antifungal treatment at both time points (104422).
• Liver cancer. It is unclear if oral selenium reduces liver cancer risk. Details: Preliminary clinical research in China suggest that taking selenium 200 mcg daily for 2-5 years can reduce the incidence of liver cancer when compared with control (74389). The benefit of selenium on prevention of liver cancer in Western countries is unknown.
• Lymphedema. It is unclear if oral selenium reduces lymphedema complications. Details: Preliminary clinical research in patients with secondary lymphedema after breast cancer surgery shows that taking a sodium selenite solution 1000 mcg daily for 1 week followed by 300 mcg daily for 2 weeks and then 200 mcg daily for a total of 15 weeks might reduce recurrence of erysipelas, a type of bacterial skin infection, when compared with placebo (15334).
• Male infertility. It is unclear if oral selenium, used alone or in combination with other antioxidants, improves pregnancy or live birth rates for couples with idiopathic male infertility. Details: Meta-analyses of 2-3 clinical trials in males with infertility show that taking selenium, alone or in combination with other antioxidants, for 12-26 weeks modestly improves sperm count and motility, but does not improve sperm morphology, when compared with placebo. Pregnancy rates and live birth rates were only studied in one clinical trial each, with no statistical evidence of benefit (109094,111459). However, the included studies may have been inadequately powered to detect a difference between groups. Studies included in the analysis used selenium 26-200 mcg daily for 3-26 weeks, either alone or in combination with vitamin A 1 mg, vitamin C 10 mg, and vitamin E 15 mg; vitamin E 400 IU and folic acid 5 mg; lycopene 6 mg, vitamin E 400 IU, vitamin C 100 mg, zinc 25 mg, folate 0.5 mg, and garlic 1000 mg; or N-acetyl-cysteine 600 mg (74526,74493,102968,109094,111459). Selenium has also been evaluated in combination with other ingredients. A retrospective study in adult males with idiopathic and varicocele-related infertility suggests that taking a combination product containing selenium 50 mcg, vitamin B12, L-carnitine, acetyl L-carnitine, citric acid, coenzyme Q10, vitamin C, zinc, and folic acid (Proxeed Plus, AltaSigma) twice daily for 6 months is associated with improvements in ejaculate volume, sperm count, sperm concentration, total motility, and progressive motility when compared to baseline. However, improvements in sperm morphology were lacking. Furthermore, patients with more severe varicocele seem to benefit most (111296). The validity of these findings is limited by a lack of comparator group. Further, it is unclear if these effects are due to selenium, other ingredients, or the combination.
• Mercury toxicity. It is unclear if oral selenium improves clearance of mercury and reduces symptoms of toxicity. Details: A small clinical trial in Chinese adults environmentally exposed to high concentrations of mercury shows that taking selenium-enriched yeast, containing selenium 100 mcg, daily for 3 months increases urinary excretion of mercury when compared with control (90351).
• Muscular dystrophy. There is limited evidence on the oral use of selenium in Duchenne muscular dystrophy. Details: Preliminary clinical research suggests that supplementation with sodium selenite 1 mg daily for 6 months does not improve disease activity in patients with muscular dystrophy (74455).
• Obesity. It is unclear if oral selenium is beneficial for weight reduction. Details: A small clinical study in adults with obesity shows that taking selenium 240 mcg daily and following a low-calorie diet for 3 months does not reduce body weight when compared with following a low-calorie diet alone (104416). Additionally, a very small clinical study in adults with overweight or obesity shows that taking L-selenomethionine 200 mcg and zinc gluconate 25 mg once daily for 8 weeks does not improve body mass index (BMI), total body fat, or fat free mass when compared with placebo (111448).
• Oral mucositis. It is unclear if oral selenium is beneficial for reducing oral mucositis in patients undergoing radiotherapy. Details: A small clinical study in patients with head and neck cancers shows that taking selenium 200 mcg twice daily for the duration of radiation therapy does not seem to reduce the incidence or severity of oral mucositis when compared with placebo (104421). It is unclear if other doses or routes of administration might be beneficial.
• Osteoarthritis. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with osteoarthritis shows that taking a specific selenium-containing combination supplement (Selenium-ACE) does not improve most clinical symptoms when compared with placebo (74449).
• Ovarian cancer. It is unclear if oral selenium reduces ovarian cancer risk. Details: Epidemiological research has found that there is no association between dietary selenium intake and the risk of developing ovarian cancer (74342).
• Overall mortality. Although oral selenium does not seem to reduce overall mortality risk in most patients, it might have benefit in patients with low nutrient intake. Details: Meta-analyses of clinical research show that selenium supplementation, alone or in combination with other micronutrients, does not reduce all-cause mortality when compared with placebo (15305,90360,97078). Selenium might also not be beneficial when used in combination with non-nutrient supplements. An additional large clinical study in elderly patients in Sweden shows that taking selenium 200 mcg daily plus coenzyme Q10 100 mg twice daily for around 5 years does not reduce the risk of all-cause mortality when compared with placebo. The baseline selenium status of these patients is unclear (92904). Despite these results, some evidence suggests that selenium used with other nutrients might have benefit in patients with low nutrient intake. In a large clinical study, selenium in combination with zinc, vitamin C, vitamin E, and beta-carotene lowered all-cause mortality risk in men, but not women, when compared with control (14109). Researchers speculate that this result occurred because men have a lower intake of dietary antioxidants than women. Another large clinical study in Chinese patients with chronically low nutrient intake shows that taking selenium with beta-carotene and vitamin E decreases stroke mortality, cancer mortality, and total mortality when compared with control (2673).
• Pancreatic cancer. It is unclear if oral selenium reduces pancreatic cancer risk. Details: Some epidemiological research has found that increased selenium intake is associated with a 34% lower risk of pancreatic cancer (97093). However, other observational research has found no association (101342).
• Pancreatitis. Although there is interest in using oral selenium for pancreatitis, there is insufficient reliable information about the clinical effects of selenium for this condition.
• Periodontitis. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with moderate or advanced periodontitis shows that taking a supplement containing selenium 30 mcg, alpha-lipoic acid, coenzyme Q10, cranberry extract, grapeseed extract, vitamin C, vitamin E, and zinc twice daily for 8 weeks in addition to standard nonsurgical therapy does not improve periodontal measures such as bleeding on probing, gingival recession, plaque index, or inflammation when compared with placebo (111708).
• Polycystic ovary syndrome (PCOS). It is unclear if oral selenium is beneficial for PCOS. Details: Most available research addressing the effects of selenium on the hormonal, metabolic, and reproductive symptoms associated with PCOS is conflicting. Meta-analyses of small clinical studies and a small clinical study in adults with PCOS show that taking selenium 200 mcg daily for 8-12 weeks might reduce total testosterone and dehydroepiandrosterone (DHEA) levels but does not seem to improve other hormone levels when compared with placebo (109096,113653,113654,113657). Additionally, a small clinical study in patients with PCOS shows that taking selenium yeast or selenium (Nature Made) 200 mcg daily for 8 weeks reduces the severity of alopecia, acne, and hirsutism when compared with placebo (109096). Research is conflicting whether selenium improves lipid profiles, glycemic indices, insulin metabolism, or anthropometric measures (109096,110596,113642,113654,113657). The effect of selenium on pregnancy outcomes in patients with PCOS who are undergoing or candidates for in vitro fertilization (IVF) is unclear. A small clinical study in patients with PCOS shows that taking selenium (Nature Made) 200 mcg daily for 8 weeks results in a significantly higher pregnancy rate of 19%, compared with 3% in those taking placebo (109096). However, another very small clinical study of the same population and dosing regimen shows that selenium does not improve IVF outcomes including pregnancy rate, endometrial thickness, number of oocytes retrieved, fertilization rate, or number of embryos when compared with placebo (113640). Selenium has also been studied in combination with other ingredients. A small clinical study in adults with PCOS shows that taking selenium 200 mcg daily for 12 weeks, along with a combination probiotic product, modestly improves subjective scores of depression, anxiety, and stress when compared with placebo. Taking this combination also modestly reduces total testosterone levels and subjective ratings of hirsutism when compared with placebo (99659). It is unclear if these effects are due to selenium, the probiotic, or the combination.
• Postoperative recovery. It is unclear if intravenous sodium selenite reduces morbidity and mortality in cardiac surgery patients. Details: A very large clinical study in adults undergoing high-risk cardiac surgery with cardiopulmonary bypass or cardioplegic arrest shows that administering intravenous high-dose sodium selenite 2000 mcg/L perioperatively, 2000 mcg/L immediately postoperatively, and then 1000 mcg/L daily in the intensive care unit (ICU) for up to 10 days does not increase the number of days alive or the number of days without persistent organ dysfunction over 30 days after surgery when compared with placebo. Additionally, intravenous sodium selenite does not reduce 30-day or 6-month mortality, intensive care unit (ICU) or hospital length of stay, or hospital readmission rates when compared with placebo (113651).
• Postpartum depression. It is unclear if oral selenium is beneficial for postpartum depression. Details: A meta-analysis of two observational studies has found that a high selenium intake is associated with a modestly reduced risk of postpartum depression. The effect of selenium supplementation on symptoms of postpartum depression is unclear. One moderate-sized clinical trial included in this publication shows that taking selenium reduces symptoms of postpartum depression (109091).
• Pregnancy-induced hypertension. It is unclear if oral selenium reduces the development of hypertension during pregnancy. Details: A small clinical study in pregnant patients shows that drinking a dietary liquid containing selenium 100 mcg daily for 6-8 weeks seems to decrease the incidence of pregnancy-induced hypertension when compared with placebo (74481).
• Premature rupture of membranes (PROM). It is unclear if oral selenium during pregnancy prevents PROM. Details: One clinical trial shows that taking selenium 100 mcg daily from the first trimester of pregnancy until delivery significantly reduces the incidence of PROM to 13%, compared to 34% with placebo (109097).
• Radiation-induced diarrhea. It is unclear if oral selenium reduces diarrhea in patients receiving radiation therapy for cancer. Details: A small clinical study in patients with cervical or endometrial cancer shows that taking selenium 500 mcg on days of radiation therapy and 300 mcg on days without radiation therapy reduces the incidence of radiation-induced diarrhea to 20.5%, compared to 44.5% in the control group not taking selenium. This benefit appears to be more pronounced in patients receiving a larger (>1302 mL) planning target volume of radiation (90355).
• Rheumatoid arthritis (RA). It is unclear if oral selenium reduces RA symptoms. Details: A small clinical study in patients with RA suggests that taking selenized yeast, providing selenium 200 mcg, daily for 90 days does not improve objective measures of RA when compared with placebo. However, there might be small improvements in quality of life measures (9763). Another small clinical study in Iranian patients with moderate to severe RA shows that taking selenium 200 mcg twice daily for 12 weeks in addition to standard treatment reduces patient-reported disease activity, difficulty in performing activities of daily living, and pain severity but does not change the number of tender or swollen joints, erythrocyte sedimentation rate, or disease activity as measured by Disease Activity Score of 28 Joints (DAS28) when compared with placebo (113648).
• Schizophrenia. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with schizophrenia shows that taking a combination of selenium (Nature Made) 200 mcg and a combination probiotic mixture (LactoCare, Zisttakhmir Company) daily for 12 weeks modestly improves general positive and negative symptoms of schizophrenia, but not positive or negative scores, when compared with placebo. There were also modest improvements in levels of high-sensitivity C-reactive protein (CRP), fasting glucose, insulin resistance, and insulin sensitivity, but not lipid parameters (109087).
• Seborrheic dermatitis. It is unclear if topical selenium disulfide shampoo is beneficial for seborrheic dermatitis. Details: A very large observational study in adults with dandruff or seborrheic dermatitis suggests that applying selenium disulfide-based shampoo 2-3 times weekly for 4 weeks improves scalp condition and reduces flaking, erythema, and irritation when compared to baseline (113652). The validity of the results is limited by the observational nature of the study and lack of comparator group. A small clinical study in adults with moderate-to-severe seborrheic dermatitis shows that applying selenium disulfide-based 1% shampoo to the scalp once weekly for 8 weeks after a 2-week treatment with corticosteroid and salicylic acid combination therapy reduces relapse rate, erythema, pruritis, adherent dandruff, and total dandruff but does not improve non-adherent dandruff when compared with a placebo shampoo (113646).
• Statin-induced myopathy. Small clinical studies suggest that oral selenium may not improve symptoms of myopathy in patients taking statins. Details: Small clinical studies in patients with statin-induced myopathy suggests that taking selenium (SelenoPrecise, Pharma Nord) 200 mcg daily with or without coenzyme Q10 for 3 months does not improve myopathy symptoms when compared with placebo (92908,92909).
• Stroke. It is unclear if intravenous selenium improves neurological outcomes following a stroke. Details: A small clinical trial in patients with a recent first ischemic stroke shows that intravenous sodium selenite pentahydrate (Selenase, Biosyn, Arzenitmittel GmbH) 2000 mcg after admission and then 1000 mcg daily for 5 days modestly improves some, but not all, measures of neurological deficits when compared with placebo (109088). Another small clinical trial in patients with a recent ischemic stroke shows that the same intervention improves some neurological outcome measures on day 7 or at an earlier discharge, but benefits were not maintained at 3 months (109093). The effects of oral selenium on neurological outcomes following a stroke have not been investigated.
• Subarachnoid hemorrhage. Intravenous selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized study in adults with aneurysmal subarachnoid hemorrhage shows that administering intravenous selenium 800 mcg and acetylcysteine 1000 mg twice daily starting within 24 hours of admission for 14 days reduces total days spent in the intensive care unit but does not change neurological outcomes, time to reach target sedation, duration of hospital stay, or need for tracheostomy when compared with intravenous placebo. Additionally, no change in radiological outcomes including hematoma or perihematomal edema volume, midline shifting, or the incidence of radiological vasospasm, angioplasty for vasospasm, or hydrocephalus was observed when compared with placebo (113644). It is unclear whether this effect is due to selenium, acetylcysteine, or the combination.
• Succinylcholine-induced myalgia. It is unclear if oral selenium is beneficial for preventing succinylcholine-induced postoperative myalgia. Details: Clinical research in patients receiving succinylcholine for a sinuscopy shows that taking a single dose of selenium 200 mcg 2 hours before anesthesia induction modestly decreases the incidence of postoperative myalgia at 24 hours. In those taking selenium, 95% of patients had no postoperative myalgia, compared with 77.5% of those taking placebo. Postoperative analgesia requirements were also modestly reduced; however, there was no difference in overall pain or the incidence of muscle twitching (109089).
• Thyroid cancer. It is unclear if oral selenium reduces the risk of thyroid cancer in most patients. Details: In 2009, the US Food and Drug Administration (FDA) approved a qualified health claim regarding selenium and thyroid cancer risk. This qualified health claim was based on one weak and limited study. The FDA has determined that it is highly uncertain that selenium supplements reduce the risk of thyroid cancer (102373). More recent observational research in postmenopausal individuals using data from the Women's Health Initiative has found that selenium intake at or above the recommended daily allowance from dietary sources or supplements is not associated with a decreased risk of thyroid cancer (110590).
• Ulcerative colitis. It is unclear if oral selenium is beneficial for ulcerative colitis. Details: A small clinical study in Iranian adults with mild-to-moderate ulcerative colitis shows that taking selenomethionine 200 mcg daily for 10 weeks in addition to standard therapy improves disease activity and quality of life and increases the percentage of patients with clinical improvement and clinical remission when compared with placebo (113643). Selenium has also been evaluated in combination with other ingredients. A clinical study in patients with ulcerative colitis shows that taking a liquid supplement containing a combination of selenium, fish oil, fructo-oligosaccharides, acacia, vitamin E, and vitamin C daily for 6 months does not improve disease activity scores when compared with placebo. However, taking the combination supplement seems to reduce the need for oral prednisone for symptom control (13757). More evidence is needed to rate selenium for these uses.

(Read more about SELENIUM)

EFFECTIVE

• Thiamine deficiency. Oral thiamine prevents and treats thiamine deficiency syndromes. Details: Thiamine deficiency is treated with oral thiamine 5-30 mg daily as a single dose or in divided daily doses for one month. For severe deficiency, thiamine up to 300 mg daily can be used (15).Thiamine deficiency can occur in people with malabsorption conditions such as alcohol use disorder, cirrhosis, and gastrointestinal diseases; in those with inadequate intake due to anorexia, nausea, and vomiting; and in those with increased requirements, including pregnancy, increased carbohydrate intake, increased physical activity, hyperthyroidism, infection, and liver disease. However, deficiency is rare with these conditions (15). The elderly might also be at increased risk for subclinical thiamine deficiency (11076).
• Wernicke-Korsakoff syndrome (WKS). Parenteral thiamine is effective for treating symptoms of WKS. Details: Parenteral administration of thiamine 5-200 mg daily for 2 days decreases the risk of developing WKS and decreases symptoms of WKS in acute alcohol withdrawal. Between 30% and 80% of alcoholics are suspected to have thiamine deficiency (11075). An optimal dose for treating WKS has not been established; however, early research suggests that a 200 mg intramuscular dose may be more effective than lower doses (11075). In contrast, a moderate-sized clinical trial in adults with a history of heavy alcohol use who were asymptomatic or symptomatic for WKS shows that there is no benefit to administering high doses (300 mg 3 times daily) compared with medium (100 mg 3 times daily) or low (100 mg daily) doses of parenteral thiamine on cognitive or neurological functioning (111690). The study may have been inadequately powered to detect a difference between groups.

POSSIBLY EFFECTIVE

• Dysmenorrhea. Oral thiamine might reduce pain in some patients with dysmenorrhea. Details: A clinical study in adolescent Iranian females with dysmenorrhea shows that taking thiamine 100 mg alone or along with fish oil 500 mg daily for 2 months moderately reduces pain intensity and duration when compared with placebo (89341). Another preliminary clinical study in Indian females 12-21 years of age with moderate to severe primary dysmenorrhea shows that taking thiamine 100 mg daily for 90 days eliminates pain in 87% of participants when compared to baseline (77820). The validity of this finding is limited by the lack of a placebo group. Furthermore, available research was conducted in India and Iran, so it is unclear if these findings are generalizable to other geographic locations.

POSSIBLY INEFFECTIVE

• Coronary artery bypass graft (CABG) surgery. Intravenous thiamine does not seem to improve outcomes after CABG surgery. Details: A small clinical study in adults undergoing CABG surgery with cardiopulmonary bypass shows that giving intravenous thiamine 200 mg immediately prior to surgery and immediately after surgery does not improve clinical outcomes or lactate levels when compared with placebo (97010). Larger doses of thiamine also don't seem to be beneficial. Another small clinical study in patients receiving CABG with cardiopulmonary bypass shows that giving thiamine 600 mg intravenously on the day of surgery, and 400 mg daily for three postoperative days, does not improve postoperative outcomes when compared with placebo (103000).
• Heart failure. Most research suggests that oral or intravenous thiamine does not improve outcomes in patients with heart failure. Details: Observational research suggests that having heart failure is associated with 2.5-fold increased odds of having thiamine deficiency, possibly because of diuretic use, intestinal malabsorption, and metabolism changes. However, it is unclear if thiamine supplementation is beneficial. A meta-analysis of 2 small clinical trials in adults with systolic heart failure and unclear thiamine status shows that thiamine 200-300 mg given orally or by IV for 7-28 days improves left ventricular ejection fraction (LVEF) by 3% when compared with control (97012). However, other meta-analyses and clinical studies in adults with heart failure with or without thiamine deficiency show that taking intravenous, intramuscular, or oral thiamine 100-500 mg daily does not improve LVEF fraction, left ventricular end-diastolic volume, dyspnea, mortality, hospitalization, or exercise tolerance when compared with placebo or control (103002,111682,111686,111688).
• Mosquito repellent. Oral thiamine does not seem to repel mosquitos. Details: Clinical research in healthy volunteers shows that taking thiamine does not improve mosquito repellency when compared with taking vitamin C as a control (18016).
• Sepsis. Intravenous or oral thiamine, alone or in combination with vitamin C and hydrocortisone, does not seem to reduce mortality or prevent organ failure in sepsis or septic shock. Details: Multiple meta-analyses of small clinical studies in patients with septic shock show that intravenous or oral thiamine 100-500 mg 2-3 times daily for 3-7 days is no better than placebo for improving mortality, end-organ damage, number of ventilator-free days, and duration of intensive care unit (ICU) stay (105443,107717,107727,111689). One meta-analysis suggests that administration of thiamine alone increases the risk of mortality in these patients (111689). Subgroup analyses including only higher quality studies also fail to show a benefit of thiamine (107717). Another recent small clinical trial in patients with septic shock shows that receiving the same dose of intravenous thiamine does not increase vasopressor-free days when compared with placebo (105441). Intravenous thiamine 200 mg every 12 hours has also been evaluated in combination with intravenous vitamin C 1.5-2 grams and hydrocortisone 50-200 mg every 6-12 hours for 4-10 days (HAT therapy). While some retrospective research found HAT therapy to be beneficial (100315,102980,111689), high-quality, prospective clinical research has shown no benefit (105447,109956,111689). Meta-analyses in patients with sepsis and septic shock shows that receiving HAT therapy does not improve mortality, kidney injury, number of ventilator-free days, or ICU length of stay when compared with control (102129,104027,104028,104032,102998,105447,109956,111642,111689). Additionally, the meta-analyses suggest that HAT therapy does not reverse shock or improve sequential organ failure assessment (SOFA) scores (109556,111642). However, one meta-analysis found that HAT therapy shortened the duration of vasopressor use when compared with placebo (111642). Long-term follow up from a study in patients with sepsis-induced respiratory and/or cardiovascular dysfunction shows that receiving HAT therapy does not improve cognitive, psychological, or functional status after 6 months and, for immediate memory scores and development of posttraumatic stress disorder, HAT therapy was less beneficial when compared with placebo (111299).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acute kidney injury (AKI). It is unclear if oral or intravenous thiamine is beneficial for treating or preventing AKI. Details: Observational research in adults admitted to the intensive care unit (ICU) with AKI has found that treatment with thiamine (dose unspecified) within the first 48 hours of admission is associated with 39% lower odds of in-hospital mortality and 28% higher odds of kidney function recovery when compared with patients that did not receive thiamine. Receiving thiamine was also associated with a 0.5-day reduction in ICU length of stay (107719).
• Anxiety. Although there is interest in using oral thiamine for anxiety, there is insufficient reliable information about the clinical effects of thiamine for this purpose.
• Cardiac arrest. It is unclear if intravenous thiamine reduces the risk of death after resuscitation from cardiac arrest. Details: A small clinical study in adults resuscitated from cardiac arrest shows that receiving intravenous thiamine 100 mg every 8 hours for 7 days does not reduce 28-day mortality when compare with a normal saline placebo (105442).
• Cardiovascular disease (CVD). It is unclear if oral thiamine is beneficial for treating or preventing CVD. Details: Population research in Korea has found that insufficient dietary thiamine intake (daily intake of less than 1.22 mg in males or 1.03 mg in females) is associated with a 16% increased odds of developing angina or myocardial infarction when compared with sufficient dietary thiamine. However, the effects of thiamine supplementation on CVD have not been studied (107725).
• Cataracts. Small studies suggest that increased dietary thiamine might help prevent cataracts. Details: Observational research has found that a high dietary intake of thiamine 10 mg daily is associated with 40% lower odds of nuclear cataracts (6378). Other population research has found that higher dietary intake of thiamine is associated with a modestly reduced risk of age-related lens opacification (14301).
• Cervical cancer. It is unclear if oral thiamine reduces the risk of developing cervical cancer. Details: Epidemiological research has found that increasing intake of thiamine from dietary and supplemental sources, along with folic acid, riboflavin, and vitamin B12, is associated with a lower odds of precancerous cervical lesions (11074).
• Child development. It is unclear if supplementing breastfeeding females with oral thiamine improves infant neurocognitive development. Details: Preliminary clinical research shows that supplementing breastfeeding females with oral thiamine, 1.2-10 mg daily for 22 weeks, starting at 2 weeks postpartum, does not improve most cognitive or neurodevelopmental scores in the child when compared with placebo. However, one subgroup analysis suggests that thiamine supplementation may improve language scores (107726).
• Cognitive function. Oral thiamine has only been studied in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in healthy, middle-aged adults shows that taking a combination product containing thiamine hydrochloride 50 mg, other group B vitamins, bacopa, and ginkgo daily for 12 weeks does not improve measures of memory, attention, cognition, mood, or stress reactivity when compared with placebo. Subgroup analysis shows a possible benefit of the combination supplementation on measures of attention in those with an optimal diet at baseline (111334). It is unclear if these findings are due to thiamine, other ingredients, or the combination.
• Coronavirus disease 2019 (COVID-19). It is unclear if intravenous or oral thiamine improves clinical outcomes in patients hospitalized with COVID-19. Details: A small observational study of adults admitted to the intensive care unit with COVID-19 has found that treatment with intravenous or oral thiamine 100 mg daily for an average of 7 days is associated with a 63% reduction in the odds of death within 30 days when compared with control. However, there was no associated reduction in duration of hospitalization or mechanical ventilation (107721). In addition, a small observational study of adults with encephalopathy that were mechanically ventilated secondary to COVID-19 has found that taking thiamine 500 mg three times daily orally for 5 days improves neurological manifestations, including ophthalmoparesis and ataxia, when compared with baseline. The validity of this study is limited by the lack of a comparator group (107722).
• Critical illness (trauma). It is unclear if oral or intravenous thiamine is beneficial in patients with critical illness. Details: A meta-analysis of critically ill patients shows that treatment with oral or intravenous thiamine 100-600 mg daily for up to 7 days does not affect the need for mechanical ventilation, duration of hospital stay, or mortality when compared with control (107727).
• Delirium. It is unclear if oral or intravenous thiamine helps to prevent or treat delirium. Details: In critically ill patients, a meta-analysis of clinical research shows that treatment with oral or intravenous thiamine 100-600 mg daily for up to 7 days reduces the odds of developing delirium by 42% when compared with control (107727). However, some observational research in adults with septic shock has found that receiving intravenous thiamine 400 mg daily with vitamin C 6 grams daily, both in divided doses, is not associated with reduced delirium when compared with control (103001). In non-critically ill, hospitalized adults with altered mental status, retrospective, observational research has also found that administration of oral or intravenous thiamine is not associated with improved cognitive function or reduced in-hospital mortality when compared with control (107723). Preliminary clinical research in adults undergoing an allogeneic hematopoietic stem cell transplant also shows that administering thiamine 200 mg three times a day intravenously for 7 days does not prevent delirium or shorten duration of delirium when compared with placebo (107718).
• Dementia. It is unclear if oral thiamine is beneficial for the prevention of dementia. Details: Observational research in patients with alcohol use disorder has found that taking thiamine is associated with a 24% to 46% lower risk of developing dementia when compared with not taking thiamine (102999).
• Depression. It is unclear if oral thiamine is beneficial in patients with depression. Details: Meta-analyses of population research in adults has found that high dietary consumption of thiamine is associated with a 10% to 31% lower risk of having depression when compared with low dietary consumption of thiamine. However, this research did not evaluate the effects of thiamine supplementation on depression (107133,107725). One small clinical study in adults with major depressive disorder shows that taking thiamine 300 mg daily in conjunction with fluoxetine 20 mg daily leads to greater improvements in depressive symptoms at 6 weeks when compared to fluoxetine with placebo. This benefit was no longer present at 12 weeks. This suggests that thiamine may accelerate improvement in symptoms during initiation of fluoxetine therapy (97013).
• Diabetes. It is unclear if oral thiamine is beneficial for type 2 diabetes or gestational diabetes. Details: A meta-analysis of 6 clinical studies in adults with type 2 diabetes shows that taking thiamine 100-300 mg or its derivative benfotiamine 120-900 mg daily for 1-3 months does not reduce glycated hemoglobin (HbA1c), fasting blood glucose, or postprandial blood glucose when compared with placebo (111681). A large, prospective cohort study in adults without type 2 diabetes suggests that the risk of new-onset diabetes is minimized in adults consuming thiamine 0.75-1.10 mg daily from the diet, while lower and higher thiamine intake levels are associated with an increased risk of new-onset diabetes (111685). Thiamine has also been studied for preventing gestational diabetes. A large, prospective cohort study in pregnant adults suggests that higher supplementation with thiamine during the first and second trimesters is associated with a lower risk of gestational diabetes when compared with lower levels of total thiamine intake. However, this effect was not found for dietary intake of thiamine, only supplementation. Additionally, the participants were mostly Han Chinese adults, limiting the generalizability of the findings to other populations (111680).
• Diabetic nephropathy. It is unclear if oral thiamine is beneficial for diabetic nephropathy. Details: A small clinical study in patients with early-stage diabetic nephropathy and microalbuminuria shows that taking thiamine 100 mg three times daily for 3 months decreases urinary albumin excretion, but does not affect glomerular filtration rate (GFR), when compared with placebo (16556).
• Diabetic neuropathy. Although there is interest in using oral thiamine for diabetic neuropathy, there is insufficient reliable information about the clinical effects of thiamine for this condition.
• Dry eye. Oral thiamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with dry eye suggests that adding unspecified doses of thiamine and mecobalamin to treatment with daily artificial tears and corticosteroid drops might slightly improve overall symptoms when compared with only artificial tears and corticosteroid drops for 1 month. There were no differences between groups at 2 months (105444). This finding is limited due to incomplete reporting and a lack of adjustment for multiple hypothesis testing.
• Dyslipidemia. It is unclear if oral thiamine is beneficial for treating or preventing dyslipidemia. Details: A meta-analysis of 3 clinical studies in adults with type 2 diabetes shows that taking thiamine 100-300 mg or its derivative benfotiamine 120-900 mg daily for 1-3 months does not improve low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides when compared with placebo (111681). Observational research in Korea suggests that insufficient dietary thiamine intake (daily intake of less than 1.22 mg in males or 1.03 mg in females) is associated with 10% higher odds of developing dyslipidemia when compared with sufficient dietary thiamine intake. However, the effects of thiamine supplementation on dyslipidemia have not been studied (107725).
• Emergence delirium. It is unclear if intravenous thiamine helps to prevent emergence delirium in patients after surgery. Details: One clinical study in adults in the intensive care unit (ICU) after gastrointestinal surgery shows that receiving intravenous thiamine 200 mg daily for 3 days is associated with up to 84% lower odds of emergence delirium on the first two days, but not on the third day, when compared with a normal saline control (105440).
• Fatigue. It is unclear if oral thiamine is beneficial in patients with fatigue. Details: A small clinical crossover study in patients with chronic fatigue and inflammatory bowel disease (IBD) shows that taking thiamine 600-1800 mg daily for 20 days reduces fatigue scores when compared with placebo (105438). Taking oral thiamine 300 mg daily for an additional 12 weeks did not seem to affect fatigue scores when compared with placebo. However, an observational follow-up study found that those who self-continued thiamine for an additional 24 weeks after the study ended reported lower fatigue scores when compared with those who did not self-continue thiamine (107720).
• Glaucoma. Although there is interest in using oral thiamine for glaucoma, there is insufficient reliable information about the clinical effects of thiamine for this condition.
• Herpes zoster (shingles). It is unclear if subcutaneous thiamine is beneficial in patients with shingles. Details: A small clinical trial shows that receiving subcutaneous thiamine 100 mg injections six times weekly for 4 weeks reduces itching by at least 30% in 67% of patients with herpes zoster. However, thiamine does not appear to significantly reduce pain in most patients (90396).
• Hypertension. It is unclear if oral thiamine is beneficial in treating or preventing hypertension. Details: Population research in Korea has found that insufficient dietary thiamine intake (daily intake of less than 1.22 mg in males or 1.03 mg in females) is associated with a 5% increased odds of developing hypertension when compared with sufficient dietary thiamine. However, the effects of thiamine supplementation on hypertension have not been studied (107725).
• Impaired glucose tolerance (prediabetes). It is unclear if oral thiamine is beneficial in patients with prediabetes. Details: A very small clinical trial in patients with prediabetes shows that taking thiamine 100 mg by mouth three times daily for 6 weeks modestly decreases 2-hour postprandial plasma glucose levels when compared to baseline and decreases fasting blood glucose levels when compared with placebo (91168).
• Kidney failure. Oral thiamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary, low-quality, clinical research in adults with kidney failure undergoing regular hemodialysis shows that taking oral thiamine 90 mg daily with folic acid 30 mg daily for 96 weeks reduces overall mortality by 67% and improves cognitive scores by 31% when compared with no intervention (107724). It is unclear if this effect is due to thiamine, folic acid, or the combination.
• Migraine headache. It is unclear if dietary thiamine is beneficial for the prevention or treatment of migraine headache. Details: A large, retrospective, cross-sectional study suggests that higher dietary intake of thiamine is associated with lower odds of severe headache or migraine, especially in females (111684). The validity of these effects is limited by the subjective outcome measures and retrospective study design.
• Pneumonia. It is unclear if thiamine is beneficial for patients with pneumonia. Details: A large retrospective cohort study in adults hospitalized with pneumonia and active alcohol use disorder suggests that parenteral administration of thiamine is associated with reduced 14-day mortality and more frequent discharges home, but not a shorter length of stay or fewer ICU transfers, when compared with no thiamine use. Furthermore, parenteral thiamine doses above 200 mg do not appear to improve mortality but may be associated with longer length of stay and less frequent discharges home when compared with low oral doses of thiamine or parenteral thiamine at doses under 200 mg (111679). The validity of these effects is limited by the retrospective study design.
• Ventilator-associated pneumonia (VAP). It is unclear if oral or parenteral thiamine is beneficial for patients with VAP. Details: A retrospective study in adults with VAP in the intensive care unit (ICU) suggests that supplementation with intravenous or oral thiamine may be associated with reduced ICU and in-hospital mortality (111683). The validity of these effects is limited by the retrospective study design. More evidence is needed to rate thiamine for these uses.

(Read more about THIAMINE)

EFFECTIVE

• Vitamin A deficiency. Oral vitamin A is effective for treatment and prevention of vitamin A deficiency. Details: Clinical and observational research in children shows that taking vitamin A orally is effective for preventing and improving symptoms of vitamin A deficiency, including xerophthalmia, night blindness, and Bitot's spots (82329,82689,82710,90773). Vitamin A deficiency can occur due to abnormal storage and transport of vitamin A in people with abetalipoproteinemia, protein deficiency, diabetes mellitus, hyperthyroidism, fever, liver disease, and cystic fibrosis (7135). However, research suggests that supplementation with vitamin A may not be necessary for most newborns with vitamin A deficiency. An observational study in newborns with vitamin A levels of 0.43-0.59 mcmol/L or >0.59 mcmol/L found that vitamin A levels increased naturally over the first six months of life, regardless of oral vitamin A supplementation. However, in infants with very low vitamin A levels (<0.43 mcmol/L), vitamin A supplementation was associated with significant increases in vitamin A levels at 6 months of age when compared with no supplementation, suggesting that only newborns with very low vitamin A levels should receive oral vitamin A (107298).

POSSIBLY EFFECTIVE

• Aging skin. Topical vitamin A (retinol) formulations seem to improve symptoms of aging skin, such as wrinkles and mottled pigmentation. Details: The vitamin A analog tretinoin (Renova) is a prescription drug approved by the U.S. Food and Drug Administration for adjunctive use in reducing fine wrinkles, hyperpigmentation, and tactile roughness of aging facial skin (103711). However, this drug is not interchangeable with non-prescription, commercially available vitamin A products, which have not been as extensively evaluated in clinical research. Although research evaluating non-prescription topical vitamin A shows benefit for reducing wrinkles, most studies have been small and used different formulations. One small study in adults over 40 years of age shows that applying a pea size amount of 0.075% retinol cream to the face daily for 26 weeks seems to reduce deep and fine wrinkling when compared with placebo. Applying a lower dose of 0.04% retinol cream for 13 weeks seems to reduce fine wrinkling to a lesser degree, with no effect on deep wrinkles, when compared with placebo cream (104458). Another small clinical study in adults over 80 years of age shows that applying 2 mL of retinol 0.4% lotion to the upper arm up to 3 times weekly for 24 weeks reduces visible wrinkles when compared with placebo (94683). Two small studies in females ages 33 to 65 show that applying retinol 0.15%, 0.3% and 0.5% in liquid crystal formulation once daily to the face for 2-3 months improves skin pigmentation, elasticity, and wrinkles when compared with baseline (103680,104464). The validity of these two studies is limited by the lack of a comparator treatment. Topical vitamin A is frequently combined with other ingredients in commercial formulations; however these combinations have rarely been studied. A small clinical study in adults over 35 years with skin aging shows that applying a cream containing retinol 0.5%, niacinamide, resveratrol, and hexylresorcinol seems to improve wrinkling and skin tone when compared with baseline (104455). Another small preliminary clinical trial in adults ages 35-65 years with periorbital lines and wrinkles shows that applying a cream containing retinol modestly improves dryness, puffiness, redness, and darkness when compared with baseline. The retinol was conjugated with lactic acid, and the cream contained other nutrient and herbal ingredients It was applied around the eyes each evening, sometimes used in combination with another product each morning (109747).
• Bronchopulmonary dysplasia. Intramuscular vitamin A may reduce the risk of bronchopulmonary dysplasia (BPD) in very low birth weight infants when given at a dose of 5000 IU three times weekly for 28 days. Lower doses do not seem to be effective. It is unclear if enteral vitamin A is beneficial for BPD. Details: A meta-analysis of 6 clinical trials in premature infants shows that intramuscular administration of vitamin A every other day or three times weekly for 28 days reduces the risk of BPD by around 33% when compared with control (107297). The results from this meta-analysis are primarily driven by a modestly sized clinical trial in very low birth weight infants which shows that intramuscular administration of vitamin A 5000 IU three times weekly for 28 days reduces the risk of BPD by 15% when compared with a sham control (82195). A subgroup analysis of this trial suggests that infants with the lowest BPD risk estimate based on gestational age, birth weight, sex, ethnicity, and oxygen levels 24 hours after birth appear to benefit more from vitamin A therapy than those with higher BPD risk estimates (107296). Previous research in this area utilized a lower dose of only 2000 IU every other day for 28 days, and showed no significant improvement in the rate of BPD (82331,82613). The evaluation of a higher dose was prompted by research noting that the lower doses evaluated in these earlier studies were unable to achieve serum retinol concentrations above 25 mcg/dL, while doses at or above 5000 IU three times weekly could reach this level (82731). Enteral vitamin A has also been investigated. Meta-analyses of two clinical trials show that supplementation with vitamin A at an average of 5,000 IU daily, staring within four days of birth, does not reduce the incidence of BPD when compared with placebo (109750,109753).
• Diarrhea. Vitamin A seems to reduce the incidence of diarrhea in young children. However, it is unclear if oral vitamin A while breastfeeding is beneficial for preventing diarrhea in nursing infants. Details: A meta-analysis of clinical research in children up to age 5 shows that vitamin A supplementation reduces the incidence of diarrhea by 15% and mortality related to diarrhea by 12% when compared with control, usually placebo or no supplementation (109755). However, one small clinical trial in breastfeeding parents shows that supplementation of vitamin A 1800 IU and ergocalciferol (vitamin D2) 600 IU daily for 2 months does not reduce the risk of diarrhea in the nursing infants when compared with placebo (107293).
• Measles. High-dose vitamin A, at recommended age-specific doses, seems to reduce mortality in children with measles under 2 years of age. Additionally, vitamin A may reduce the incidence of measles in children up to 5 years of age who are at risk for vitamin A deficiency. Details: Vitamin A deficiency is a known risk factor for severe measles, as well as measles-related morbidity and mortality. The use of vitamin A supplementation for the treatment of measles has been studied mostly in resource-limited countries with increased risk for vitamin A deficiency. However, measles infection has also been shown to deplete vitamin A stores, leading to recommendations for vitamin A supplementation in acute measles, regardless of geographic location (115976). Meta-analyses of clinical research show that taking vitamin A does not reduce mortality in children with measles when all ages and/or doses are considered (82373,82502). However, a sub-analysis of 3 studies that utilized a higher dose of 200,000 IU orally daily for two days, in children under 2 years of age who were hospitalized with measles, shows that this dosing regimen reduces the relative risk of mortality by about 60% when compared with placebo (82373,82502). Additionally, vitamin A supplementation in children with measles may reduce the risk of some complications, such as croup (82373). Most studies in these analyses were conducted in regions with high measles case-fatality rates; the benefit of vitamin A supplementation in regions with lower case-fatality rates, such as the United States, is unclear. Based on these data, the World Health Organization (WHO) recommends treatment with vitamin A, using age-specific doses, for all children with acute measles (115966). The American Academy of Pediatrics (AAP) also recommends the administration of age-specific doses to all children with measles, regardless of severity, as follows: 200,000 IU daily for 2 days in children at least one year of age, 100,000 IU daily for 2 days in children 6-12 months of age, and 50,000 IU daily for 2 days in children under 6 months old. In children with clinical symptoms of vitamin A deficiency, an additional age-specific dose is recommended 2-6 weeks later (115977). Vitamin A supplementation has also been studied in apparently healthy children living in regions at high risk for vitamin A deficiency. A meta-analysis of 6 clinical studies shows that taking vitamin A reduces the incidence of measles in children ages 6 months to 5 years. These studies provided vitamin A supplementation either as a single high dose or as three high doses over one year. In 3 studies, vitamin A was given in conjunction with measles vaccination; vaccination status was not provided for the other studies (109755). The WHO and AAP do not recommend the use of vitamin A for measles prevention. Instead, routine measles vaccination is recommended. Additionally, for people over 6 months of age with recent measles exposure who are unimmunized or insufficiently immunized, immediate measles vaccination is recommended (115966,115977).
• Night vision. Oral vitamin A as retinyl palmitate seems to reduce night blindness during pregnancy in malnourished patients. Details: Clinical research shows that taking vitamin A (as retinyl palmitate) 23,000 IU weekly before and during pregnancy reduces pregnancy-related night blindness by 37% in malnourished patients (6154). Some evidence suggests that zinc supplements might potentiate the effects of vitamin A in restoring sight in zinc-deficient pregnant patients affected by night blindness (8630).
• Oral leukoplakia. High-dose oral vitamin A seems to reduce oral leukoplakia lesions in patients that chew tobacco and/or betel nut. Details: Clinical research in patients with tobacco and/or betel nut chewing habits shows that taking oral vitamin A 200,000-300,000 IU weekly for 6-12 months seems to result in remission of leukoplakia lesions in over 50% of participants when compared with placebo (34674,82617). However, it is unknown if vitamin A prevents the development of oral cancer from oral leukoplakia lesions.
• Overall mortality. In children at risk for vitamin A deficiency, oral vitamin A seems to reduce mortality. However, it does not seem to reduce mortality in healthy adults. Details: Despite previous debate on whether the programs supplying high-dose vitamin A in low- and middle-income countries with prevalent vitamin A deficiency are safe and effective for reducing child mortality, most experts, including World Health Organization, recommend high-dose vitamin A supplementation for those children (95055,95724,97170,109755). Meta-analyses including 8-18 clinical studies show that vitamin A supplementation reduces all-cause mortality by about 12%-26% in children 6 months to 5 years of age (82559,95055,115748), but does not seem to reduce mortality in neonates or children 1-6 months of age (115748). Notably, the largest clinical trial conducted to date (Deworming and Enhanced Vitamin A; DEVTA), which involved one million preschool children and was included in one of the previously discussed meta-analyses, suggests that high-dose vitamin A supplementation does not reduce mortality (90773). However, this trial was limited due to under-resourcing and undetermined patient consent and treatment compliance (90773). Adult mortality is not reduced by vitamin A supplementation. In fact, some evidence even shows that vitamin A supplementation increases mortality when administered to healthy adult patients or those with a stabilized disease (15305,34622,90775).
• Postpartum complications. Oral vitamin A seems to reduce postpartum diarrhea and mortality in malnourished patients. Details: A large clinical study in malnourished pregnant patients in Nepal shows that taking vitamin A (as retinyl palmitate) 23,000 IU weekly before, during, and after pregnancy reduces the occurrence of blood and mucus in the stool by 93% and the occurrence of diarrhea by up to 90% during the first 6 months postpartum when compared with placebo (2581). Another clinical study in the same population shows that taking vitamin A (as retinyl palmitate) 23,000 IU weekly before and during pregnancy reduces pregnancy-related mortality by 40% when compared with placebo (6153).
• Retinitis pigmentosa. Oral vitamin A supplementation in children with retinitis pigmentosa seems to slow retinal function decline. Details: Observational and clinical research in children with retinitis pigmentosa shows that taking an age-adjusted dose of vitamin A, up to a maximum dose of 15,000 IU daily, modestly attenuates the decline in retinal function when compared with control (83,97167,103677).
• Ulcerative colitis. Oral vitamin A supplementation in patients with ulcerative colitis seems to improve clinical response and mucosal healing. Details: A clinical study in adults with symptomatic ulcerative colitis despite treatment with 5-aminosalicylic acid shows that taking vitamin A 25,000 IU daily for 2 months reduces disease severity and increases the rate of clinical response and mucosal healing when compared with placebo. The number needed to treat (NNT) for clinical response is 3; the NNT for mucosal healing is 5 (100329).
• Wrinkled skin. Topical vitamin A (retinol) formulations seem to improve photodamage and wrinkles. Details: The vitamin A analog tretinoin (Renova) is a prescription drug approved by the U.S. Food and Drug Administration for adjunctive use in reducing fine wrinkles, hyperpigmentation, and tactile roughness of facial skin (103711). This drug is not interchangeable with non-prescription, commercially available vitamin A products, which have not been as extensively evaluated in clinical research. Some research in females ages 35-65 with moderately wrinkled and photoaged skin suggests that commercially available retinol formulations might reduce wrinkles and skin roughness similarly to tretinoin. One study used retinol serum starting at a concentration of 0.25% and increased to 1% over 3 months, compared with tretinoin cream 0.025% gradually increased to 0.1% (103671), while another study compared a gradual release tri-retinol 1.1% cream applied daily for 3 months to tretinoin 0.025% cream (104456). Commercial retinol also seems to be beneficial when compared with placebo. A meta-analysis of 6 clinical studies including a total of 352 females over 30 years of age with mild to moderate photodamage shows that applying stabilized retinol 0.1% to the face once or twice daily for 8-12 weeks reduces overall photodamage when compared with placebo. Retinol also reduced uneven skin tone, brown spots, wrinkles and fine lines on the forehead, cheek, and undereye, and crow's feet. Five of the six studies used a split-face design, with each participant serving as their own control. Skin assessments were performed by a single dermatologist in all six studies (114500).

POSSIBLY INEFFECTIVE

• Atopic disease. Supplementation with oral vitamin A does not seem to reduce the risk of atopy. Details: Clinical research in infants born in Guinea-Bissau shows that a single dose of vitamin A does not reduce the incidence of atopy when compared with placebo (90779,90780). Furthermore, giving a single dose of vitamin A to some infants, such as low birth weight infants and infants given Bacille Calmette-Guerin (BCG) vaccination, was associated with increased atopy and wheeze (90779).
• Fetal and premature infant mortality. Giving oral vitamin A to malnourished adults during pregnancy and postpartum does not seem to reduce fetal, early infant, or first year mortality. Giving oral or intramuscular vitamin A to the infant also does not seem to reduce mortality in most patients. Details: Most meta-analyses of clinical research in malnourished patients suggest that vitamin A supplementation during pregnancy or postpartum does not reduce fetal, early infant, or first year mortality (6152,34601,34602,34627,82479,82566,82567,90774,90776,90782,90784,95057,109750,109753). Also, giving vitamin A supplements or intramuscular vitamin A to low birth weight infants does not appear to reduce mortality in these patients (82195,82431,82498,90778,90781,95053,107296,107297). Furthermore, vitamin A supplementation in term infants from low or middle income countries also does not appear to reduce the risk of mortality at 6 or 12 months of age when compared with placebo (95054,103674). Some evidence from a meta-analysis of clinical research shows that vitamin A supplementation may reduce the risk of mortality at 6 months in Asian infants, although it appears to increase the risk of mortality at 6 months in studies conducted in Africa. It also appears to increase the risk of mortality in female term infants by 12 months (95054).
• Intestinal parasite infection. Oral high-dose vitamin A does not seem to prevent reinfection with intestinal parasites. Details: Clinical research in children living in Malaysia that were given albendazole 400 mg daily for 3-4 days for parasitic worms, shows that adding a single dose of vitamin A 200,000 IU does not help to prevent reinfection when compared with placebo (90772).
• Melanoma. Oral vitamin A in patients with resected melanoma does not seem to improve survival and disease recurrence. Details: A clinical study in patients with completely resected melanoma shows that taking vitamin A 100,000 IU daily for 18 months does not increase disease-free survival when compared with no supplementation (82670).
• Miscarriage. Oral vitamin A given to the mother does not prevent miscarriage or stillbirth. Details: A meta-analysis of clinical research shows that maternal supplementation with oral vitamin A, either alone or in combination with other vitamins, prior to or during early pregnancy does not reduce the risk of miscarriage or stillbirth when compared with control (104462).
• Sepsis. Most research shows that oral vitamin A does not reduce the risk of sepsis in premature infants. Details: A meta-analysis of three clinical trials in premature infants shows that providing supplemental enteral vitamin A 1500-5000 IU daily, starting within four days of birth, does not reduce the incidence of sepsis when compared with placebo (109753).
• Tuberculosis. Oral vitamin A does not seem to improve tuberculosis disease duration or mortality. Details: Low levels of vitamin A are common in patients with tuberculosis. However, taking vitamin A 2000 IU to 200,000 IU by mouth for 2-24 months does not improve symptoms, decrease disease duration, or reduce mortality when compared with placebo in these patients (82570,103668,109754). This may be due to the fact that vitamin A levels may normalize following the initiation of tuberculosis treatment, even without additional vitamin A supplementation.

LIKELY INEFFECTIVE

• Head and neck cancer. Oral vitamin A taken for 2 years does not seem to improve survival or prevent head and neck cancer recurrence. Details: A large clinical study n patients with a history of head and neck cancer shows that taking vitamin A as retinyl palmitate 300,000 IU daily for 1 year, and followed by 150,000 IU daily for another year, does not reduce the risk of second primary tumors or tumor recurrence when compared with placebo. Also, vitamin A does not seem to improve survival or event-free survival (1710).
• HIV transmission. Oral vitamin A does not reduce vertical HIV transmission risk. There is some concern that vitamin A might increase HIV transmission through breast milk. Details: Observational and intervention research shows that taking vitamin A orally does not decrease the risk of HIV transmission to the fetus during pregnancy, to newborns during delivery, or to infants during early breast-feeding (6376,82470,95059). Preliminary clinical research also shows that vitamin A supplementation of pregnant adults with HIV infection might increase the risk of HIV transmission to their babies through breast milk (9801).
• Lower respiratory tract infections. Oral vitamin A does not reduce the risk for lower respiratory tract infections in children. It is unclear if supplementation of oral vitamin A while breast-feeding reduces the risk of lower respiratory tract infections in nursing infants. Details: Taking vitamin A by mouth does not prevent or reduce symptoms of lower respiratory tract infections, such as cough and fever, in children (82288,82443). Furthermore, some research shows that vitamin A is associated with a slight increase in the risk of respiratory tract infections when administered to children with adequate nutritional status (82288). Additionally, one small clinical trial in breast-feeding parents shows that supplementation of vitamin A 1800 IU and ergocalciferol (vitamin D2) 600 IU daily for 2 months does not reduce the risk of febrile illness or respiratory tract infections in the nursing infants when compared with placebo (107293).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although prescription vitamin A analogs are approved to treat acne, it is unclear if non-prescription topical vitamin A products help with acne symptoms. Details: The high-dose vitamin A analogs adapalene (Differin) and tazarotene (Tazorac) are prescription drugs approved by the US Food and Drug Administration for the treatment of acne (103712,103713). These drugs are not interchangeable with non-prescription, commercially available vitamin A products, such as retinol, which have not been extensively evaluated in clinical research. A small preliminary clinical trial in adolescents and young adults with mild to moderate acne shows that applying topical benzoyl peroxide 2.5% each morning and a topical retinol plus salicylic acid product each evening for 12 weeks modestly improves acne severity and other measures of complexion when compared with baseline. All patients also used the same cleanser twice daily (109748). The validity of this finding is limited by the lack of a comparator group.
• Alcohol-related liver disease. Oral vitamin A has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with acute alcoholic hepatitis shows that taking vitamin A in combination with coenzyme Q10 and other vitamins and minerals daily for 6 months does not improve survival when compared with placebo (61392).
• Asthma. It is unclear if oral vitamin A is beneficial for preventing asthma in children. Details: An observational study in children has found that higher dietary intake of vitamin A is associated with a lower risk of asthma. Children in the highest quartile of vitamin A intake (median of 2267 IU daily) at 7 years of age had improved lung function and 32% lower odds of asthma at 11-14 years of age when compared with children in the lowest quartile of vitamin A intake (median of 870 IU daily) (107291).
• Atopic dermatitis (eczema). It is unclear if supplementation of oral vitamin A while breast-feeding is beneficial for preventing eczema in nursing infants. Details: One small clinical trial in breast-feeding parents shows that supplementation of vitamin A 1800 IU and ergocalciferol (vitamin D2) 600 IU daily for 2 months does not reduce the risk of eczema in the nursing infants when compared with placebo (107293).
• Autism spectrum disorder. It is unclear if oral vitamin A is beneficial for improving symptoms of autism. Details: Children with autism spectrum disorder are at increased risk for vitamin A deficiency, and vitamin A levels have been inversely associated with autism symptoms. Preliminary clinical research shows that taking a single dose of vitamin A 200,000 IU slightly improves emotional response, communication, and other symptoms when compared to baseline (97168). The lack of a control group limits the validity of these findings. Another preliminary clinical study in children with autism and vitamin A deficiency shows that taking vitamin A 50,000 IU weekly for 6 months, but not as a single dose of 200,000 IU, seems to improve social impairment scores when compared with control. Controls were children with autism without vitamin A deficiency that did not take a supplement (104459).
• Breast cancer. Although vitamin A intake has been associated with a reduced risk for breast cancer, it is unclear if vitamin A supplements are beneficial. Details: Epidemiological evidence has found an association between high intake of vitamin A and a reduced risk of breast cancer. A meta-analysis of epidemiological research has found that the adults with the highest intake of vitamin A, either from diet alone or also from supplements, reduces the odds of developing breast cancer by 16% when compared with the lowest intake (1444,34610,109752). However, the effects of supplemental vitamin A, specifically, are unclear.
• Cataracts. It is unclear if oral vitamin A is beneficial for cataract prevention. Details: Observational research has found that higher dietary intake of vitamin A is associated with a modestly reduced risk of cataracts (6378,112095). Also, other population research has found that the highest dietary intake of vitamin A is associated with a 17% lower risk of cataracts when compared with the lowest intakes (90786). However, there is conflicting evidence regarding the association between blood levels of vitamin A and the risk of cataracts (90786,90944). It is not known if supplemental vitamin A is beneficial for this purpose.
• Cervical cancer. It is unclear if oral vitamin A is beneficial for cervical cancer prevention. Details: A meta-analysis of clinical research shows that increased vitamin A levels in the blood or higher vitamin A intakes are associated with a reduced risk of cervical cancer. However, this effect is observed when both forms of vitamin A, either retinol or carotenoids, are considered. When only the retinol form is considered, vitamin A supplementation does not seem to reduce the risk of cervical cancer (34613,109752). Also, a meta-analysis of epidemiological research has found that vitamin A intake, either from diet alone or supplements, does not affect the risk of cervical cancer (109752).
• Chemotherapy-induced diarrhea. It is unclear if oral vitamin A helps to prevent diarrhea caused by chemotherapy. Details: A very small clinical study in children receiving chemotherapy shows that taking vitamin A orally does not seem to prevent GI adverse effects, including diarrhea and mouth pain, when compared with control (9802).
• Child development. Oral vitamin A might improve growth and development in children with vitamin A deficiency, but not in those with good nutritional status. Details: Supplementing with vitamin A 60 mg for up to 9 years does not promote or improve child growth in children with appropriate nutritional status (20132). However, in children with vitamin A deficiency, supplementation with vitamin A may improve growth (82246).
• Chronic obstructive pulmonary disease (COPD). There is limited evidence on the oral use of vitamin A in patients with emphysema. Details: Observational research has found that consuming recommended amounts of vitamin A in the diet is associated with 33% lower odds of developing emphysema (103678).
• Cognitive function. It is unclear if oral vitamin A is beneficial for cognitive function. Details: A large clinical trial in schoolchildren in Ethiopia, most without vitamin A deficiency, shows that taking vitamin A 200,000 IU at baseline and after 5 months improves working memory, but not other measures of cognitive development, when compared with placebo (113904). However, results are unlikely to be clinically significant.
• Colorectal adenoma. Oral vitamin A has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination supplement containing selenium, zinc, vitamin A, vitamin C, and vitamin E orally daily for 5 years or until the recurrence of an adenoma reduces the risk of recurrent large-bowel adenomas by about 40% when compared with placebo in patients with large-bowel adenomas (92903). It is not clear if this benefit is due to vitamin A or other constituents.
• Colorectal cancer. It is unclear if oral vitamin A is beneficial for colorectal cancer prevention. Details: Taking vitamin A alone or in combination with beta-carotene does not seem to reduce the risk of colorectal cancer (12185).
• Corneal abrasion. It is unclear if topical vitamin A is beneficial for preventing corneal abrasion during surgery. Details: A clinical study in patients undergoing general anesthesia for non-ophthalmic surgery shows that applying a specific vitamin A containing gel (Ziyang® Vitamin A Palmitate Eye Gel, Shenyang Xingqi Pharmaceutical Co., Ltd) to the ocular surface prior to eye taping decreases evidence of corneal abrasion and increases tear production 30 minutes after surgery when compared with taping without vitamin A gel. However, by 24 hours there was no difference between the two eyes (114501).
• Coronary artery bypass graft (CABG) surgery. It is unclear if oral vitamin A improves recovery after CABG surgery. Details: Preliminary clinical research shows that taking vitamin A 5000 IU daily (as retinol palmitate) for 21 days starting on the day of CABG surgery reduces time in intensive care after surgery by 46% to 69% compared to a control group not given vitamin A (90783). Supplementation with vitamin A also improves total hospitalization time for those patients with adequate zinc status (90783).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral vitamin A is beneficial for the treatment of mild to moderate COVID-19. Details: Clinical research in COVID-19 outpatients treated with hydroxychloroquine shows that taking vitamin A 25,000 IU daily for 10 days modestly reduces the number of patients with symptoms of fever, body ache, and fatigue when compared with placebo. However, there was no effect on the number of patients with cough, shortness of breath, lack of appetite, chest pain, diarrhea, loss of smell, or headache (109745).
• Depression. It is unclear if oral vitamin A is beneficial for depression. Details: A meta-analysis of observational research has found that dietary intake of vitamin A is inversely associated with depression. The highest intake of vitamin A was associated with a 17% reduced risk of depression when compared with the lowest intake. Also, vitamin A intake was lower in individuals with depression (109743). The effect of vitamin A supplementation is unclear.
• Esophageal cancer. It is unclear if oral vitamin A is beneficial for esophageal cancer prevention. Details: Observational research has found that higher beta-carotene and vitamin A intake is associated with a reduced risk of esophageal cancer (34551,103675). However, evidence from higher-quality clinical research shows that taking vitamin A in combination with beta-carotene does not reduce the risk of esophageal cancer (12185).
• Gastric cancer. It is unclear if oral vitamin A is beneficial for gastric cancer prevention. Details: Taking vitamin A alone and in combination with beta-carotene does not seem to reduce the risk of gastric cancer (12185).
• Glaucoma. It is unclear if oral vitamin A is beneficial for glaucoma prevention. Details: Meta-analyses of observational research suggests that a high dietary intake of vitamin A is associated with a 37% reduced risk or 42% lower odds of glaucoma when compared with a low intakes (109742,112095).
• Graft-versus-host disease (GVHD). It is unclear if taking vitamin A prior to hematopoietic stem cell transplant (HSCT) decreases the incidence of acute or chronic GVHD. Details: A clinical study in patients 1-28 years of age with serum vitamin A levels below the 75th percentile shows that taking a single oral dose of vitamin A 4000 IU/kg (maximum dose: 250,000 IU) approximately 1 week before allogenic HSCT decreases the incidence of chronic GVHD at 1 year to 5%, compared with 12.5% in those taking placebo. However, patients who took vitamin A did not have a lower rate of acute GVHD or acute gastrointestinal GVHD at 100 or 180 days when compared with placebo. All patients in this study with low vitamin D levels also received vitamin D supplementation per an institutional protocol (114498).
• HIV/AIDS. It is unclear if oral vitamin A is beneficial for improving HIV/AIDs outcomes. Details: A meta-analysis of clinical trials and population research shows that maternal vitamin A supplementation of mothers with poor vitamin A status at baseline does not influence child or maternal mortality, hospitalization rate, or HIV/AIDS progression. However, pediatric vitamin A supplementation seems to decrease mortality rates in children with HIV/AIDS when compared with placebo (34529,95059).
• HIV/AIDS-related diarrhea. It is unclear if oral vitamin A is beneficial for preventing diarrhea associated with HIV. Details: A large clinical trial shows that taking vitamin A can decrease the rate of diarrhea-specific mortality by up to 92% in vitamin A-deficient children with or without HIV/AIDS (1465). However, a meta-analysis of clinical research shows that taking vitamin A does not significantly reduce diarrhea-specific mortality when only children with HIV/AIDS are considered (82511). But vitamin A does appear to reduce overall mortality in these children by 50% to 63% (1465,82511).
• Human papillomavirus (HPV). It is unclear if topical or oral vitamin A is beneficial for the resolution of genital warts caused by HPV. Details: A meta-analysis of small clinical trials in patients with genital warts suggests that the oral prescription drugs isotretinoin and etretinate might promote resolution of warts when compared with baseline. However, the topical prescription drug tretinoin 0.05% cream does not seem to help (104460). These drugs are not interchangeable with non-prescription, commercially available vitamin A products, such as retinol.
• Infant development. It is unclear if intramuscular vitamin A improves the development of low birth weight infants. Details: A meta-analysis of clinical research shows that giving intramuscular vitamin A to very low birth weight infants reduces the risk of chronic lung disease at 36 weeks postmenstrual age by about 13% compared to control (95053). Preliminary clinical research also shows that giving intramuscular vitamin A along with inhaled nitric oxide gas for 3 weeks to low birth weight infants on mechanical ventilation might improve mental development at one year in some of these patients when compared with inhaled nitric oxide gas alone (90778). However, a meta-analysis of clinical research shows that intramuscular vitamin A does not improve neurodevelopment in very low birth weight infants (95053).
• Iron deficiency anemia. It is unclear if oral vitamin A is beneficial for the prevention or treatment of anemia due to iron deficiency. Details: Some research in children and pregnant adults without anemia shows that taking vitamin A increases plasma levels of hemoglobin and ferritin, and may reduce the risk of developing anemia (9518,34627). However, another study in pregnant patients, half of whom had anemia at baseline and half of whom did not have anemia, shows that taking 3000 mcg retinol orally in combination with iron and folate does not improve hemoglobin or erythropoietin concentrations when compared with taking iron and folate (9188). In preterm infants with existing anemia, taking vitamin A 5000 IU and vitamin B complex 40 mg daily improves serum ferritin, hemoglobin, and reticulocyte levels and reduces the need for blood transfusions when compared with taking either vitamin alone. Taking vitamin A alone, however, does not improve these outcomes (100330).
• Leukemia. It is unclear if oral vitamin A is beneficial for leukemia prevention. Details: Preliminary clinical research in adults with chronic myelogenous leukemia shows that taking a specific vitamin A product (Aquasol, Armour Pharmaceuticals) 50,000 IU orally daily in combination with busulfan therapy does not significantly increase progression-free survival or overall survival when compared with busulfan alone. Furthermore, supplementation with vitamin A plus busulfan seems to increase the percentage of patients who experience grade 2 toxicity by about 5-fold when compared with busulfan alone (82652).
• Liver cancer. It is unclear if oral vitamin A is beneficial for liver cancer prevention. Details: Population research has found that vitamin A supplementation or serum levels of vitamin A are not associated with the risk of liver cancer (97169).
• Lung cancer. It is unclear if oral vitamin A is beneficial for lung cancer treatment or prevention. Details: A large clinical trial in patients with existing lung cancer shows that vitamin A 300,000 IU daily for one year followed by 150,000 IU daily for a second year does not increase survival (1710). However, some clinical research shows that high-dose vitamin A 300,000 IU daily following curative lung cancer resection reduces the risk of new primary tumors in patients heavily exposed to tobacco (7875). Observational research on the relationship between vitamin A and lung cancer risk is conflicting. One large observational study suggests that higher dietary intake of vitamin A is associated with a lower risk of lung cancer. Specifically, each quartile increase in dietary vitamin A intake was associated with a 15%, 25%, and 37% lower relative risk of lung cancer when compared with the lowest intake. However, taking vitamin A in supplement form was not associated with lung cancer risk (112096). Other observational research has found that increased dietary intake of vitamin A is not associated with a reduced risk of lung cancer (35628). Furthermore, supplementation with vitamin A and beta-carotene seems to increase the risk of lung cancer in smokers or those exposed to asbestos (2642,34675).
• Malaria. It is unclear if oral vitamin A is beneficial for reducing symptoms of malaria in young children. Details: Taking vitamin A orally seems to help decrease symptoms of malaria in children less than 3 years of age living in endemic areas (1464). However, other clinical research shows that single doses of vitamin A 100,000 to 200,000 IU do not improve coma resolution, convulsions, fever, parasite clearance, or mortality in infants and children less than 5 years of age with cerebral malaria (90785).
• Multiple sclerosis-related fatigue. It is unclear if oral vitamin A is beneficial for reducing fatigue in patients with multiple sclerosis. Details: Preliminary clinical research in patients with relapsing-remitting multiple sclerosis receiving interferon beta-1a shows that taking vitamin A 25,000 IU (as retinyl palmitate) (Zahravi Pharmaceutical) daily for 6 months followed by 10,000 IU daily for 6 months, improves physical, cognitive, and psychosocial fatigue when compared with placebo (95052).
• Necrotizing enterocolitis (NEC). A meta-analysis of several small clinical trials suggests that intramuscular vitamin A does not seem to prevent NEC. Details: A meta-analysis of 3 small clinical studies in very low birth weight infants shows that intramuscular administration of vitamin A 1500-5000 IU every other day or three times weekly for 28 days does not reduce the risk of NEC when compared with a control (107297).
• Non-Hodgkin lymphoma. It is unclear if oral vitamin A is beneficial for non-Hodgkin lymphoma prevention. Details: Population research has found that intake of vitamin A at levels above 2330 mcg daily is associated with a 17% lower risk of non-Hodgkin lymphoma when compared with those whose daily intake of vitamin A is less than 642 mcg per day (90945).
• Nonmelanoma skin cancer. It is unclear if oral vitamin A is beneficial for nonmelanoma skin cancer prevention. Details: Observational research over 26 years found that higher dietary vitamin A intake is associated with a 12% reduced risk for cutaneous squamous cell carcinoma in healthy patients when compared with lower vitamin A intake (101673).
• Oral clefts. It is unclear if oral vitamin A is beneficial for oral cleft prevention. Details: A meta-analysis of observational research has found that periconceptional use of vitamin A, from diet and/or supplements, is associated with a 13% reduced incidence of cleft lip alone or with a cleft palate, but is not associated with the risk of cleft palate alone, in the child (109751).
• Osteoarthritis. Oral vitamin A has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with osteoarthritis shows that taking a specific product containing vitamin A in combination with selenium, vitamin C, and vitamin E (Selenium ACE, Carls-Berghs Farmaceutiska AB) does not appear to alleviate symptoms when compared with placebo (74449).
• Ovarian cancer. It is unclear if oral vitamin A is beneficial for ovarian cancer prevention. Details: Most observational research has found that increased dietary intake of vitamin A is associated with a reduced risk of developing ovarian cancer (9193,103679,109752). The most recent meta-analysis of epidemiological research has found that adults with the highest intake of vitamin A, either from diet alone or supplements, reduces the odds of developing ovarian cancer by 19% when compared with the lowest intake (109752).
• Pancreatic cancer. It is unclear if oral vitamin A is beneficial for pancreatic cancer prevention. Details: A meta-analysis of observational research has found that higher intake of vitamin A is associated with a reduced risk of pancreatic cancer; however, this benefit appears to be limited to only hospital-based cases and studies conducted in Europe (95060). In contrast, a meta-analysis of clinical research shows that taking vitamin A in combination with beta-carotene does not reduce the risk of pancreatic cancer (12185).
• Parkinson disease. It is unclear if oral vitamin A prevents Parkinson disease development. Details: Population research has found that blood levels or dietary intake of vitamin A are not associated with the risk of Parkinson disease (91164).
• Photoreactive keratectomy. Oral vitamin A has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that taking a specific product (Evitex capsules, Alcon) containing vitamin A along with vitamin E seems to improve healing after photoreactive keratectomy. High dose (50,000 to 75,000 IU) vitamin A in the form of retinol palmitate taken daily with vitamin E (alpha-tocopheryl nicotinate) 460-590 mg daily seems to accelerate re-epithelialization, reduce haze formation, and improve visual acuity in patients undergoing laser surgery for myopia (348).
• Pneumonia. Oral vitamin A does not seem to prevent mortality related to pneumonia in children. However, it is unclear if vitamin A reduces symptom severity and hospitalization in children. Details: Clinical research in children living in developing countries shows that taking vitamin A orally does not prevent mortality related to pneumonia (1466,82362,82504,82717,109749). However, the evidence related to symptom duration and severity is mixed. A large study and early meta-analyses show that vitamin A does not prevent pneumonia or decrease the severity or length of hospitalization in children with pneumonia (1466,82362,82504,82717). A more recent meta-analysis also shows that giving vitamin A to children at or below 5 years of age does not affect the duration of hospitalization (109755). The best evidence to date comes from a recent meta-analysis of randomized clinical trials. This meta-analysis shows that, when given in combination with conventional therapy to children up to 10 years of age, vitamin A reduces the duration of symptoms including fever, cough, lung rale, and shortness of breath, as well as the duration of hospitalization and time to a negative X-ray, when compared with conventional therapy alone (109749). However, the number of trials evaluating each endpoint is small and more research is needed to confirm these findings.
• Prematurity. It is unclear if vitamin A reduces the duration of hospitalization for premature infants. Details: A meta-analysis of four randomized controlled trials in preterm infants shows that providing supplemental enteral vitamin A 1500-5000 IU daily, starting within four days of birth, does not reduce the duration of hospitalization when compared with placebo (109750).
• Prostate cancer. It is unclear if oral vitamin A is beneficial for prostate cancer prevention. Details: Observational studies suggest that dietary intake of vitamin A is not associated with a reduced risk of prostate cancer (14134).
• Psoriasis. It is unclear if topical vitamin A is beneficial for psoriasis symptoms. Details: The vitamin A analog tazarotene (Tazorac) is a prescription drug that is approved by the U.S. Food and Drug Administration to treat stable plaque psoriasis covering up to 20% body surface area (103713). This drug is not interchangeable with non-prescription, commercially available vitamin A products, such as retinol.
• Radiation proctopathy. It is unclear if oral vitamin A is beneficial for reducing chronic radiation proctopathy symptoms. Details: A small clinical study in patients experiencing chronic radiation proctopathy caused by pelvic radiotherapy shows that taking retinol palmitate 10,000 IU daily for 90 days might reduce rectal symptoms when compared with placebo (82350).
• Retinopathy of prematurity. Most small studies show that oral or intramuscular vitamin A does not reduce the risk of retinopathy of prematurity (ROP). Details: A meta-analysis of 4 small clinical studies in very low birth weight infants shows that intramuscular administration of vitamin A 2000-10,000 IU every other day or three times weekly, or oral vitamin A 2000 IU daily, for 28 days does not reduce the risk of ROP when compared with a control (107297). Another meta-analysis of clinical research shows that providing supplemental enteral vitamin A 1500 IU or an average of 5000 IU daily, starting within four days of birth, does not reduce the incidence of severe ROP (109750,109753). However, a very small clinical study in preterm infants, which was not included in the meta-analysis, shows that receiving retinol palmitate drops 3000 IU/kg daily for 28 days reduces the risk of ROP by 88% when compared with no treatment (103672).
• Upper respiratory tract infection (URTI). It is unclear if vitamin A is beneficial for the prevention or treatment of URTIs in young children. Details: A meta-analysis of 3 low-quality clinical studies in children under 7 years of age living in low- to middle-income countries found that there is no association between vitamin A supplementation and rate of acute URTI, although this finding was considered to be of low certainty. There was insufficient data to determine whether vitamin A may reduce the severity of URTI symptoms (114499). The interpretation of findings is limited by high heterogeneity of the study populations and dosing regimens, as well as variability in selected outcomes.
• Urinary tract infections (UTIs). It is unclear if adding oral vitamin A to antibiotic therapy is beneficial for symptoms of acute pyelonephritis in young females. Details: A small clinical study in females 2-12 years of age with a first occurrence of acute pyelonephritis shows that taking vitamin A 1500 units/kg daily for 10 days in conjunction with antibiotics decreases the duration of fever by about 1.3 days and reduces urinary frequency by about 1.5 episodes per day when compared to taking placebo with antibiotics. Taking vitamin A might also reduce the occurrence of moderate or severe renal scarring after 6 months when compared with placebo (100327). The validity of these findings is limited by small study size and a high dropout rate.
• Warts. It is unclear if topical or oral vitamin A improves the resolution of viral warts. Details: A meta-analysis of observational and clinical research in patients with viral warts suggests that receiving prescription oral retinoids (isotretinoin, acitretin, etretinate) seems to produce a 61% rate of wart resolution. Prescription topical retinoids seems to produce a 64% rate of wart resolution (104461). These drugs are not interchangeable with non-prescription, commercially available vitamin A products, such as retinol. More evidence is needed to rate vitamin A for these uses.

(Read more about VITAMIN A)

EFFECTIVE

• Imerslund-Grasbeck disease. Intramuscular vitamin B12 is effective for patients with this condition. Details: Administering intramuscular vitamin B12 (hydroxocobalamin) 1 mg daily for 10 days, followed by monthly injections for the remainder of a patient's life, is effective for treating familial selective vitamin B12 malabsorption (Imerslund-Grasbeck disease) (15,82862).
• Vitamin B12 deficiency. Administering vitamin B12 orally, intramuscularly, or intranasally is effective for preventing and treating vitamin B12 deficiency. Details: Vitamin B12 deficiency has varying definitions but is often defined as vitamin B12 (cobalamin) levels less than 180-200 pmol/L (or 240 pg/mL). Some believe that only intramuscular vitamin B12 is effective for treating vitamin B12 deficiency. However, clinical research shows that oral therapy increases cobalamin levels similarly to intramuscular administration, even in patients with pernicious anemia or malabsorption, if a high enough dose is given (2909,2911,2915,9335,82832) (82836,82949,82860,103976,103972,107141,107144). Some evidence suggests that the most effective oral dose is between 647-1032 mcg daily (13106). However, in certain situations, intramuscular treatment might be more appropriate. Guidelines by the British Committee for Standards in Hematology recommend only intramuscular vitamin B12 for initial treatment of severe vitamin B12 deficiency in patients with pernicious anemia, malabsorption disorders, or neurological involvement (94722). Intramuscular vitamin B12 is also appropriate in patients with diarrhea or vomiting and those likely to be nonadherent (103972). Vitamin B12 deficiency is especially common in older adults, primarily due to lack of intrinsic factor and malabsorption (2915,2919,9335). Daily supplementation with vitamin B12 50-100 mcg might be needed to correct deficiency (10126), while daily doses of 25-37.5 mcg help to maintain normal levels over time (9335). In addition to supplements, foods such as milk and bread fortified with vitamin B12 can be used and are approximately 55% to 60% absorbed by people over 60 years of age (10124). Vitamin B12 deficiency is also common in patients that have had gastric surgery, including gastrectomy and bariatric surgery (107144,107145). Taking vitamin B12 in the doses found in multivitamins or generic vitamin B supplements does not seem to prevent vitamin B12 deficiency following bariatric surgery (107145). However, taking methylcobalamin 500 mcg daily is beneficial for treating vitamin B12 deficiency associated with a total gastrectomy and taking cyanocobalamin 5000 mcg daily is beneficial for preventing vitamin B12 deficiency following gastric bypass (107144). Other people at risk for vitamin B12 deficiency include strict vegetarians who eat no animal products (vegans) and people with increased vitamin B12 requirements associated with pregnancy, thyrotoxicosis, hemolytic anemia, hemorrhage, malignancy, and hepatic and kidney disease. Moderate consumption of animal products may not be sufficient to restore and maintain vitamin B12 levels, especially in adolescents who had consumed macrobiotic (vegan type) diets for the first 6 years of life. High dietary intake of vitamin B12 or supplements is usually needed in order to restore and maintain optimal vitamin B12 levels in these adolescents (10125).

LIKELY EFFECTIVE

• Cyanide poisoning. Intravenous hydroxocobalamin (Cyanokit) is likely effective as an antidote for patients with suspected or known cyanide toxicity due to inhalation, ingestion, or skin exposure. Details: Treatment of cyanide poisoning with hydroxocobalamin (Cyanokit) up to 10 grams has been approved by the US Food and Drug Administration (FDA) and recommended by the Australian Resuscitation Council (82870,82905,82906). Hydroxocobalamin is also FDA-approved for treating cyanide toxicity during pregnancy (82904).

POSSIBLY EFFECTIVE

• Canker sores. Sublingual or topical vitamin B12 seems to reduce canker sore symptoms. Details: Clinical research in patients with canker sores shows that applying a topical ointment containing vitamin B12 500 mcg in four divided doses daily for 2 days reduces pain levels by 80% when compared with a control ointment not containing vitamin B12 (96176). Other preliminary clinical research shows that taking vitamin B12 1000 mcg sublingually daily for 6 months reduces the duration of canker sore outbreaks, the number of ulcers, and level of pain when compared with placebo in patients with normal vitamin B12 levels (17242).
• Hyperhomocysteinemia. Oral vitamin B12 in combination with folic acid, and sometimes with vitamin B6, reduces homocysteine levels. Details: While folic acid 0.5-5 mg daily lowers fasting homocysteine levels by an average of 25%, adding vitamin B12 0.5 mg daily produces an additional decrease of about 7% on average (6883,9400,9401,9405,9409,50145,107136). Vitamin B12 in combination with folic acid and other vitamins also reduces homocysteine levels in patients with kidney failure, sickle cell disease, and those receiving nitrous oxide general anesthesia (1489,6883,6884,7289,7881,9324,9414,9415,9416,9481,82941). Some researchers recommend routine use of vitamin B12 with homocysteine-lowering regimens to avoid the risk of neuropathy in people with undetected vitamin B12 deficiency (9405). Using vitamin B12 alone has a limited effect on homocysteine levels, and probably only in those people with vitamin B12 deficiency (2147,9410,9512). Hyperhomocysteinemia is considered by some to be an independent risk factor for atherosclerosis, recurrent thromboembolism, deep vein thrombosis, myocardial infarction, and ischemic stroke (1899,2147,3323,9402,9405,9408,9409). Clinical research suggests that supplementation with folic acid, pyridoxine, and vitamin B12 decreases homocysteine levels and reduces the atherosclerosis progression in patients at risk for atherosclerosis when compared with placebo (50133,50056,82806). However, other research suggests that elevated homocysteine levels may be a marker, as opposed to a cause, of vascular disease (11387,11388). A 5 µmol/L increase in plasma homocysteine increases the risk of cerebrovascular disease by 50%, and the odds of coronary heart disease by 60% and 80% in males and females, respectively (9407,9411). However, it is not clear if reducing homocysteine levels results in reduced cardiovascular morbidity and mortality (1489,6883,6884,9400,9405,9409,96417). Folic acid, vitamin B6, and vitamin B12 supplementation can reduce total homocysteine from 13.4 to 11 µmol/L. However, this reduction does not seem improve endothelial function or help with secondary prevention of death or myocardial infarction, and some research even suggests an increase in cardiovascular disease (CVD) risk (11387,13482,50373,50314,97619). There is also some debate about whether supplementation with homocysteine-lowering B vitamins can reduce the risk of stroke. A number of large clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with CVD or impaired kidney function (11387,13482,50423,83050,96150). However, a more recent meta-analysis of 10 clinical trials including over 44,000 patients shows that B vitamin supplementation reduces the relative risk of stroke by 10% when compared with placebo in patients at risk or with a history of CVD (97619). Also, a meta-analysis in adults with a history of stroke shows that B vitamin supplementation modestly reduces the relative risk of stroke recurrence by 13% and vascular death by 11% when compared with placebo (107136).
• Postherpetic neuralgia. Subcutaneous injections of vitamin B12 seem to reduce postherpetic neuralgia symptoms. Details: Clinical research in patients with subacute herpetic neuralgia shows that subcutaneous injection of vitamin B12 (methylcobalamin) 1000 mcg six times weekly for 4 weeks reduces pain when compared with oral vitamin B12 or subcutaneous lidocaine (90394). Another clinical study shows that administering local subcutaneous injections of methylcobalamin 1000 mcg plus lidocaine up to 20 mg daily for 12 injections over 14 days, starting within 7 days of the onset of subacute ophthalmic herpetic neuralgia, decreases the mean pain score by 63% to 79% when compared with intravenous lidocaine and intramuscular methylcobalamin. Less than 2 patients need to be treated to achieve a pain reduction to ≤3 out of 10. Healing of rash, itching, numbness, and tingling were also improved (96175). Additional clinical research in patients with postherpetic pain and itching shows that this same dosing regimen of subcutaneous vitamin B12 reduces pain and analgesic requirements when compared to baseline (90396).

POSSIBLY INEFFECTIVE

• Age-related cognitive decline. Oral vitamin B12 does not seem to improve cognitive function in older adults when used alone or in combination with other B vitamins. Details: Taking vitamin B12 100-1000 mcg plus folic acid 400-2000 mcg, with or without vitamin B6 3-50 mg, daily for up to about 2 years does not seem to improve tests of cognitive function in adults aged 65 or older, most of whom do not report cognitive impairment at baseline (14392,50225,50510,90392,107140). Also, supplementation with vitamin B12 does not seem to improve cognitive function in elderly individuals with low vitamin B12 levels (12305).
• Alzheimer disease. Oral vitamin B12, when used in combination with other B vitamins, does not seem to improve cognitive function in patients with Alzheimer disease. Details: Clinical research in patients with probable Alzheimer disease using routine medication shows that taking vitamin B12 1 mg, folic acid 5 mg, and vitamin B6 25 mg daily for 18 months does not have a beneficial effect on cognitive function or the severity of disease when compared with placebo. In this study, all patients were consuming a folate-fortified diet (50319). Also, a meta-analysis of clinical research in elderly adults with mild cognitive impairment or dementia shows that taking vitamin B12, usually with other B vitamins, does not improve cognitive function (50510). Observational research has also found that higher vitamin B12 intake over 3 years in a population consuming a folate-fortified diet is not associated with a decreased risk of developing Alzheimer disease (15270). In contrast, preliminary clinical research in patients with probable Alzheimer disease who are not consuming a folate-fortified diet shows that taking vitamin B12 50 mcg daily plus folic acid 1.2 mg daily for 6 months modestly improves some measures of cognitive performance and decreases levels of homocysteine when compared with placebo (107150). More research is needed to determine if any changes in this latter study are clinically relevant.
• Cataracts. Oral vitamin B12 does not seem to reduce cataract development. Details: Clinical research in women with existing cardiovascular disease (CVD) or at increased risk of CVD shows that taking a combination of folic acid 2.5 mg daily, vitamin B6 50 mg daily, and vitamin B12 1 mg daily for an average of 7.3 years does not reduce the risk of cataracts and seems to increase the risk of cataract extraction by 28% when compared with placebo (96149).
• Circadian rhythm sleep disorders. Oral vitamin B12 does not seem to improve sleep disorders. Details: Oral vitamin B12 (methylcobalamin) does not seem to be effective for treating delayed sleep phase syndrome. Methylcobalamin 0.5-1 mg three times daily, with or without bright light therapy, also does not seem to help people with primary circadian rhythm sleep disorders (1344,1345,1346,1347,1348).
• Cognitive impairment. Oral vitamin B12 does not seem to be beneficial for older adults with cognitive impairment. Details: A meta-analysis of clinical research in elderly adults with mild cognitive impairment or dementia shows that taking vitamin B12, usually with other B vitamins, does not improve cognitive function (50510). One clinical trial in elderly people with memory complaints shows that taking a combination of B vitamins, including folic acid 0.8 mg, vitamin B12 0.5 mg, and vitamin B6 (form not specified) 20 mg daily for 24 months reduces cerebral atrophy in the gray matter regions associated with Alzheimer disease by up to seven-fold when compared with placebo. However, this protection does not occur in patients with the lowest average blood levels of homocysteine (90374).
• Fall prevention. Oral vitamin B12 does not seem to reduce the risk of falls. Details: Clinical research shows that taking B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg, daily for 2 years does not prevent falls when compared with placebo in elderly individuals also taking vitamin D (96148).
• Osteoporosis. Oral vitamin B12 does not seem to reduce the risk of osteoporotic fractures. Details: Clinical research in elderly patients or patients with a history of cerebrovascular disease shows that taking vitamin B12 500 mcg and folic acid 0.4-2 mg, with or without vitamin B6 25 mg, daily for 2-3 years does not seem to reduce the risk for osteoporotic fractures when compared with placebo (90377,90393). A 5-7 year follow-up of this research has also found no benefit (103981).
• Physical performance. Oral vitamin B12 does not seem to improve physical performance in older adults. Details: Clinical research shows that taking B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg, daily for 2 years does not increase hand strength or improve performance such as walking when compared with placebo in elderly individuals also taking vitamin D (96148).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large-scale clinical study shows that taking vitamin B12 1000 mcg, folic acid 2.5 mg, and vitamin B6 50 mg daily, reduces the risk of developing AMD in females over 40 years of age with a history of cardiovascular disease (CVD) or at least three risk factors for CVD. Those who took this combination for an average of 7.3 years had a 34% reduced risk of developing AMD and a 41% reduced risk of visually significant AMD when compared with placebo (14620). It is unclear if this effect is due to vitamin B12, other ingredients, or the combination.
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). It is unclear if high-dose intramuscular vitamin B12 improves the prognosis of ALS. Details: A clinical study in patients with ALS symptoms for 3 years or less shows that intramuscular vitamin B12 (methylcobalamin) 25-50 mg twice weekly for 3.5 years does not slow functional decline or increase the time until ventilation or death when compared with placebo. However, other clinical research in patients with early-stage ALS shows that intramuscular methylcobalamin 50 mg twice weekly for 16 weeks is associated with slower functional decline and a longer period of time until death or full ventilation when compared with placebo (104947,111556). These effects seem to be particularly notable in fine and gross motor skills, but not bulbar or respiratory functions. Furthermore, vitamin B12 and riluzole slowed clinical progression of ALS more than riluzole alone (111556).
• Angioplasty. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some evidence suggests that vitamin B12 400 mcg, folic acid 1 mg, and vitamin B6 10 mg daily can decrease the rate of restenosis in patients treated with balloon angioplasty (8009,9412,34540). However, this combination does not seem to be as effective for reducing restenosis in patients after coronary stenting (8009). An intravenous loading dose of folic acid, pyridoxine, and vitamin B12 followed by oral administration of folic acid 1.2 mg, pyridoxine 48 mg, and vitamin B12 60 mcg daily after bare metal coronary stenting also does not seem to reduce restenosis and might actually increase restenosis (12150,12151,34540). Due to the lack of evidence of benefit and potential for harm, this combination of vitamins should not be recommended for patients receiving coronary stents (12151). It is unclear if any effects are due to vitamin B12, other ingredients, or the combination.
• Anxiety. Although there is interest in using oral vitamin B12 for anxiety and panic attacks, there is insufficient reliable information about the clinical effects of vitamin B12 for these uses.
• Asthma. Although there is interest in using oral vitamin B12 for asthma, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Atherosclerosis. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with intermediate risk for coronary heart disease shows that taking vitamin B12 100 mcg, aged garlic extract 250 mg, folic acid 300 mcg, vitamin B6 12.5 mg, and L-arginine 100 mg daily for 12 months reduces coronary artery calcium progression when compared with placebo (88385). It is unclear if this effect is due to vitamin B12, other ingredients, or the combination.
• Atopic dermatitis (eczema). It is unclear if topical vitamin B12 reduces the severity of eczema. Details: Preliminary clinical research shows that applying a specific topical vitamin B12 0.07% cream (Regividerm) twice daily reduces the extent and severity of atopic dermatitis when compared with placebo (15765).
• Attention. Although there is interest in using oral vitamin B12 for improving attention and focus, there is insufficient reliable information about the clinical effects of vitamin B12 for this use.
• Cancer. It is unclear if oral vitamin B12 reduces overall cancer risk when used in combination with other B vitamins. Details: An ancillary clinical study in middle-aged and elderly adults with cardiovascular disease shows that taking a combination of vitamin B12 (cyanocobalamin) 0.02 mg, folic acid 0.56 mg, and vitamin B6 3 mg, with or without eicosapentaenoic acid (EPA) 400 mg plus docosahexaenoic acid (DHA) 200 mg, for a median of 4.7 years does not reduce the risk of cancer when compared with placebo (90666). An additional secondary analysis of clinical research in patients recovering from stroke or transient ischemic attack shows that taking vitamin B12 500 mcg, folic acid 2 mg, and vitamin B6 25 mg daily for around 3.4 years does not reduce the risk of cancer when compared with placebo (90378). The validity of these findings is limited because the studies were not designed nor adequately powered to test for cancer risk.
• Cardiovascular disease (CVD). Oral vitamin B12, taken along with other B vitamins, does not seem to improve secondary prevention of death or myocardial infarction in patients with CVD. However, it might slightly reduce the risk of stroke. Details: Overall evidence from clinical research and meta-analyses shows that taking vitamin B12 in combination with folic acid and/or vitamin B6 does not seem to reduce the risk for secondary death or myocardial infarction in patients with or at risk for CVD (11387,13482,34540,50423,83050,90379,97619). In fact, some research suggests that long-term supplementation with vitamin B6, folic acid, and vitamin B12 for secondary prevention increases the risk of CVD by 20% despite lowering homocysteine levels by 30% (13482). However, other research shows that taking vitamin B12 in combination with other B vitamins modestly reduces the risk of stroke, although results are conflicting (11387,13482,50423,83050,96150,96165,97619,107136). It is unclear which specific combination of B vitamins, if any, might be optimal for reducing stroke risk and which patients are most likely to benefit. In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) approved a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368).
• Cervical cancer. It is unclear if oral vitamin B12 reduces cervical cancer risk. Details: Some epidemiological evidence has found that increasing vitamin B12 intake from dietary and supplement sources, along with folic acid, thiamine, and riboflavin, might decrease the risk of precancerous cervical lesions (11074). Also, an analysis of two case control studies has found that increased intake of vitamin B12 is associated with a 75% reduced odds of cervical cancer (34609).
• Chemotherapy-induced peripheral neuropathy. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients receiving chemotherapy shows that a combination of B vitamins that includes vitamin B12 (cyanocobalamin) 1000 mcg, taken daily starting one week prior to treatment and finishing 12 weeks after treatment is completed, does not prevent peripheral neuropathy when compared with placebo (96173).
• Child development. It is unclear if oral vitamin B12 is beneficial for child development. Details: Population research has found that daily dietary intake of less than 2.26 mcg vitamin B12 in the third trimester of pregnancy is associated with an increased risk of poorer outcomes in the offspring for some measures of speech and mathematics ability, including vocabulary at 24 months, combining words at 38 months, speech intelligibility at 6 years, and math comprehension between ages 8-11 years, when compared with dietary intakes of at least 2.26 mcg daily. There was no association between prenatal vitamin B12 intake and reading or spelling abilities, vocabulary at other ages, or full-scale Intelligence Quotient (IQ) at ages 8 or 15 (107143). Furthermore, a very large clinical study in infants of pregnant adults, 71% of whom were deficient in vitamin B12 at baseline, shows that taking vitamin B12 50 mcg daily starting in early pregnancy (<15 weeks gestation) until 6 months postpartum does not improve neurodevelopment as measured by language, motor, socioemotional, or cognitive scores at 12 months old and may worsen early motor performance at 8-12 weeks when compared with placebo. However, the negative effects on motor performance resolved by 6 and 12 months of age (112431).
• Child growth. Oral vitamin B12 taken by pregnant adults does not seem to be beneficial for infant growth. Details: A very large clinical study in infants of pregnant adults, 71% of whom were deficient in vitamin B12 at baseline, shows that taking vitamin B12 50 mcg daily starting in early pregnancy (<15 weeks gestation) until 6 months postpartum does not improve the infant's linear growth, length, or weight at 12 months of age (112431).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral vitamin B12 reduces the risk of COPD. Details: Clinical research in patients with COPD shows that taking vitamin B12 500 mg daily for 8 weeks modestly improves endurance on the cycle ergometer, but does not improve oxygen consumption, when compared with placebo (96172).
• Cognitive function. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in healthy, middle-aged adults shows that taking a combination product containing vitamin B12, other B vitamins, bacopa, and gingko biloba twice daily for 12 weeks does not improve measures of memory, attention, cognition, mood, or stress reactivity when compared with placebo (111334).
• Colorectal cancer. It is unclear if oral vitamin B12 reduces colorectal cancer risk. Details: Some epidemiological evidence has found that increased dietary intake of vitamin B12 is associated with a reduced risk of developing colorectal cancer (90383). However, preliminary clinical research shows that taking vitamin B12 1 mg, folic acid 2.5 mg, and vitamin B6 50 mg daily for up to 7.3 years does not reduce the risk of colorectal adenoma in females at high risk for cardiovascular disease (90389). Furthermore, a secondary analysis of clinical research in elderly patients suggests that taking vitamin B12 500 mcg and folic acid 400 mcg daily for 2 years might increase the risk of colorectal cancer when compared with placebo (90393).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral vitamin B12 is beneficial for patients with COVID-19. Details: A small observational study in hospitalized patients with COVID-19 pneumonia has found that higher plasma vitamin B12 levels may be associated with an increased risk of transfer to intensive care or death than lower plasma levels. However, when multivariate regression was conducted, only patient age was associated with worsened outcomes. Additionally, the total study population was small, with only nine of 49 patients experiencing the worsened outcomes (107138).
• Dementia. It is unclear if oral vitamin B12 reduces the risk of developing dementia. Details: A large cohort of Danish adults has found that vitamin B12 levels or intake does not seem to impact the risk of developing Alzheimer disease or other dementias (104922). However, vitamin B12 might be beneficial in specific patient populations. A small observational study in patients with Parkinson disease has found that higher vitamin B12 levels (648.5 ng/L) are associated with a lower risk of developing dementia when compared with lower vitamin B12 levels (452 ng/L) (103975). It is not yet known if supplementation with vitamin B12 reduces the risk for dementia in these patients.
• Depression. It is unclear if oral vitamin B12 is beneficial for reducing depression risk. Details: A meta-analysis of epidemiological research has found that the highest dietary intake of vitamin B12 is associated with a 14% reduced risk of depression. However, in a sub-analysis, this association was not significant in males (107133). In contrast, one epidemiological study in older males included in the analysis has found that daily dietary intake of at least 4.79 mcg vitamin B12 is linked with a 58% lower risk of depression when compared with daily intake of less than 3.16 mcg. In this study, this inverse association was not observed in females (96168). Other observational research has found that low-normal serum vitamin B12 levels are associated with a 3.8 times increased risk for depression during pregnancy when compared with normal vitamin B12 levels (102384). It is unclear if increased intake of vitamin B12 through the diet or supplements reduces the risk for depression or is beneficial for treating symptoms of depression in any population. However, a meta-analysis of clinical research in elderly populations shows that supplementation with vitamin B12 100-1000 mcg daily, usually in combination with folic acid 400-2000 mcg daily, does not reduce symptoms of depression. Most individuals in these studies were not specifically diagnosed with depression (107140).
• Diabetes. It is unclear if oral vitamin B12 improves glycemic indices or prevents loss of skeletal muscle in patients with diabetes. Details: A small clinical study in patients with diabetes in India who are stabilized on metformin and/or a sulfonylurea shows that taking vitamin B12 (methylcobalamin) 500 mcg with or without folic acid 5 mg daily for 8 weeks seems to reduce glycated hemoglobin (HbA1C) by 1.3% to 1.5%, compared with a 0.3% increase with placebo (104917). This study is limited due its small sample size and lack of blinding. In elderly adults with type 2 diabetes, population research has found a lower dietary intake of vitamin B12 (average of 11.2 mcg daily) in individuals with a loss of skeletal muscle mass of at least 1.2%, compared with an average intake of 13.4 mcg daily in those with a skeletal muscle mass loss of less than 1.2%. However, further analysis determined that any relationship between vitamin B12 intake and loss of skeletal muscle mass was only significant in individuals with insufficient energy intake overall (107151).
• Diabetic neuropathy. Small clinical studies suggest that oral vitamin B12 may modestly improve pain in patients with diabetic neuropathy. Details: Two small clinical studies in patients with diabetic peripheral neuropathy show that taking vitamin B12 (methylcobalamin) 1-1.5 mg for 4-12 months modestly improves pain when compared with baseline or placebo (82841,104923). Some research also shows that vitamin B12 may be beneficial in combination with other ingredients. Studies have evaluated products containing vitamin B12 (methylcobalamin or cyanocobalamin), benfotiamine, and vitamin B6 daily for 9-12 weeks (82931,82939); and vitamin B12 (methylcobalamin) 2 mg, folic acid (L-methylfolate) 3 mg, and vitamin B6 (pyridoxal-5'-phosphate) 35 mg (Metanx; Pamlab) daily for 24 weeks (90375).
• Diarrhea. It is unclear if oral vitamin B12 is beneficial for reducing diarrhea in children. Details: Preliminary clinical research in children aged 6-30 months from low- and middle-income countries shows that taking vitamin B12 at twice the recommended dietary allowance, with or without folic acid, does not reduce the risk for diarrhea when compared with placebo (90391).
• Fatigue. It is unclear if intramuscular vitamin B12 is beneficial for improving well-being in those with fatigue or tiredness. Details: A small crossover trial in patients complaining of tiredness or fatigue shows that receiving intramuscular injections of vitamin B12 (hydroxocobalamin) 5 mg twice weekly for 2 weeks seems to improve general well-being and happiness, and has a trend toward improving fatigue, when compared with placebo (10127). The validity of this study is limited by a large drop-out rate and unstandardized outcome measures.
• Hearing loss. Oral vitamin B12 has only been evaluated in combination with adenosine triphosphate; its effect when used alone is unclear. Details: A small observational study in adults with idiopathic sudden sensorineural hearing loss has found that taking vitamin B12 1.5 mg with adenosine triphosphate 300 mg daily for 8-16 weeks is associated with modestly reduced hearing loss at 4-6 months after starting treatment when compared with taking the combination for less than 8 weeks (104924). This finding is limited due to its observational nature and lack of a control group.
• Hepatitis C. It is unclear if intramuscular vitamin B12 is beneficial for sustaining viral response in patients with chronic hepatitis C infection. Details: A small clinical study in patients with chronic hepatitis C infection shows that intramuscular vitamin B12 (cyanocobalamin) 5000 mcg every 4 weeks along with standard care improves sustained viral response when compared with standard of care alone (90386).
• Hypertriglyceridemia. It is unclear if oral vitamin B12 is beneficial for reducing triglyceride levels. Details: Some evidence shows that taking vitamin B12 7.5 mcg with fish oil 5 grams might be superior to fish oil alone when used daily to reduce total serum cholesterol and triglycerides. This suggests vitamin B12 might have an independent effect in lowering serum cholesterol and triglycerides, but further investigation is needed to confirm this effect (8694).
• Hypotension. It is unclear if oral vitamin B12 is beneficial for treating hypotension. Details: A meta-analysis of 3 observational studies in patients hospitalized with hypotension secondary to cardiac surgery vasoplegia suggests that administration of intravenous vitamin B12 (hydroxocobalamin) is associated with an 8 mmHg higher mean arterial pressure (MAP) at 1 hour but no change in vasopressor dosage at 1 hour or mortality rate when compared with methylene blue (112264). The validity of these findings is limited by the inclusion of only retrospective studies.
• Infant development. It is unclear if taking oral vitamin B12 during pregnancy is beneficial for improving infant development. Giving oral vitamin B12 to infants does not seem to be beneficial. Details: Clinical research shows that supplementation with vitamin B12 50 mcg daily from less than 14 weeks gestation until 6 weeks postpartum does not improve cognitive development in infants by 9 months of age when compared with placebo (96174). When these children were evaluated at 30 months of age, a very small benefit of vitamin B12 on expressive language was identified; however, there was no effect on cognition, receptive language, fine motor skills, or gross motor skills (100169). It is unknown whether a longer duration of postpartum supplementation or supplementation in specific populations might be beneficial. Vitamin B12 supplementation in infants has also been evaluated. A large clinical trial in marginally stunted Nepalese infants aged 6-11 months shows that giving vitamin B12 (cyanocobalamin) 2 mcg daily for 12 months reduces homocysteine levels, but does not improve motor or cognitive development, when compared with placebo (104926).
• Inflammatory bowel disease (IBD). Although there is interest in using oral vitamin B12 for IBD, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Lung cancer. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: The association between vitamin B12 and lung cancer is unclear. Some population research found no relationship between blood levels of vitamin B12 and lung cancer (9454). However, other observational research involving over 5,000 case-control pairs found that higher vitamin B12 levels are linked with an increased risk for lung cancer (102383). It is unclear if increased intake of vitamin B12, either through the diet or supplementation, directly affects the risk of lung cancer.
• Male infertility. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A retrospective study in adult males with idiopathic and varicocele-related infertility suggests that taking a combination product containing vitamin B12 1.5 mcg, L-carnitine, acetyl L-carnitine, citric acid, selenium, coenzyme Q10, vitamin C, zinc, and folic acid (Proxeed Plus) twice daily for 6 months is associated with improvements in ejaculate volume, sperm count, sperm concentration, total motility, and progressive motility in patients with idiopathic infertility when compared to baseline. However, improvement in sperm morphology was lacking. Furthermore, patients with more severe varicocele seem to benefit most, especially with regard to progressive motility (111296). The validity of these findings is limited by a lack of comparator group. Further, it is unclear if these effects are due to vitamin B12, other ingredients, or the combination.
• Mastalgia. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients with mastalgia shows that taking a combination of vitamin B12 as methylcobalamin 100 mg, gamma-linolenic acid, and vitamin C daily for 12 weeks does not improve the proportion of patients with minimal or no pain when compared with placebo (111059).
• Multiple sclerosis (MS). Although there is interest in using oral vitamin B12 for MS, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral vitamin B12 is beneficial for NAFLD. Details: A small clinical study in adults with NAFLD shows that taking vitamin B12 1000 mcg daily for 12 weeks reduces serum levels of homocysteine but has no effect on serum aminotransferases, measures of steatosis, fibrosis scores, fasting blood glucose, serum insulin, measures of insulin resistance, triglycerides, low-density lipoprotein (LDL) cholesterol, or high-density lipoprotein (HDL) cholesterol when compared with placebo (111555).
• Pancreatic cancer. It is unclear if oral vitamin B12 is beneficial for reducing the risk of pancreatic cancer. Details: Most population research has found that increased intake of vitamin B12, as a supplement or in the diet, is not associated with a reduced risk of pancreatic cancer (9327,104927). However, a small, retrospective population study in which smoking and non-smoking adults recalled past eating habits found that increased dietary intake of vitamin B12 is associated with a 33% reduction in pancreatic cancer risk (97976). These conflicting findings may be related to study methodology, as well as the age, gender, or smoking status of the included patients.
• Periodontitis. Although there is interest in using oral vitamin B12 for periodontitis, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Peripheral neuropathy. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific product containing vitamin B12 3 mcg, folic acid 400 mcg, and uridine monophosphate 50 mg (Keltican) daily for 60 days reduces pain by 44% and decreases analgesic use by over 75% when compared to baseline in patients with peripheral neuropathy, including those with lumbar/lumbosacral radiculopathy, sciatic pain, and cervical radiculopathy (90384). The validity of this finding is limited by the lack of a control group. Furthermore, it is unclear if the benefits are due to vitamin B12, other ingredients, or the combination.
• Psoriasis. Topical vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that a specific cream containing vitamin B12 and avocado oil (Regividerm, Regeneratio Pharma AG) reduces symptoms of psoriasis as effectively as calcipotriol ointment (Psorcutan) after 12 weeks of therapy. The vitamin B12 combination cream also causes less irritation than calcipotriol (14909). It is unclear if the benefits are due to vitamin B12, other ingredients, or the combination.
• Respiratory tract infections. A small study suggests that oral vitamin B12 does not reduce the rate of respiratory tract infections in children. Details: Preliminary clinical research in children aged 6-30 months from low-and middle-income countries suggests that taking vitamin B12 at twice the recommended dietary allowance with or without folic acid does not reduce the risk for lower respiratory tract infections when compared with placebo (90391).
• Schizophrenia. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination of vitamin B12 400 mcg and folic acid 2 mg daily for 16 weeks improves negative symptoms when compared with placebo in patients with schizophrenia who have persistent symptoms and a specific genetic variant of the folate transporter gene FOLHI. This variant normally results in reduced folate absorption. However, in patients without this genetic variant, folate is not beneficial with respect to negative symptom improvement (90387).
• Sickle cell disease. Oral vitamin B12 has only been evaluated in combination with other B vitamins; its effect when used alone is unclear. Details: Preliminary clinical research in adults with sickle cell disease shows that taking vitamin B12 4.2-6 mcg, folic acid 700 mcg, and vitamin B6 4.2-6 mg daily might lower homocysteine levels. However, it is unknown if this will reduce the risk of endothelial damage in these patients (9324).
• Stroke. It is unclear if oral vitamin B12, either alone or with other B vitamins, is beneficial for stroke prevention. Details: Epidemiological research has found that people with a higher intake of vitamin B12 from dietary sources do not have a reduced risk of ischemic or hemorrhagic stroke (14316). A number of clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with cardiovascular disease (CVD) or impaired kidney function (11387,13482,50420,50423,83050,90379,90380,96150). However, a more recent meta-analysis of 10 clinical trials including over 44,000 patients shows that B vitamin supplementation modestly reduces the relative risk of stroke by 10% when compared with placebo in patients at risk or with a history of CVD (97619). This meta-analysis differed from some of the earlier analyses due to the inclusion of several additional clinical trials. Also, a meta-analysis in adults with a history of stroke shows that B vitamin supplementation modestly reduces the relative risk of stroke recurrence by 13% and vascular death by 11% when compared with placebo (107136). In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Unfortunately, even after the publication of higher quality research, it is still unclear which specific combination of B vitamins is optimal and which patients are most likely to benefit. One network meta-analysis suggests that a combination of folic acid and vitamin B6 lowers the risk of stroke more effectively than B vitamin mixtures that include vitamin B12 (96165). However, this analysis is limited because it didn't account for dosing. Another meta-analysis suggests that exposure to low, but not high, amounts of vitamin B12 (cyanocobalamin) seems to reduce stroke risk (96150).
• Tinnitus. It is unclear if intramuscular vitamin B12 is beneficial in patients with tinnitus. Details: A small clinical study shows that intramuscular vitamin B12 2500 mcg weekly for 6 weeks reduces tinnitus severity by 22% when compared to baseline in patients with chronic tinnitus and vitamin B12 deficiency, but not in patients with normal levels of vitamin B12. Vitamin B12 does not improve pitch or volume in either group of patients (96170). The validity of this finding is limited by the lack of a control group.
• Venous thromboembolism (VTE). It is unclear if oral vitamin B12 is beneficial for preventing VTE. Details: Epidemiological research has found that low levels of vitamin B12 are associated with an increased risk for VTE. However, clinical trials evaluating the use of B vitamins for prevention of VTE have shown conflicting results (90398). More evidence is needed to rate vitamin B12 for these uses.

(Read more about VITAMIN B12)

EFFECTIVE

• Pyridoxine-dependent epilepsy. Intravenous vitamin B6 is effective for controlling pyridoxine-dependent seizures. Details: Pyridoxine-dependent seizures are a rare type of refractory seizures in neonates that do not respond to anticonvulsant drugs. These seizures are typically controlled within minutes of intravenous administration of pyridoxine, a form of vitamin B6. Pyridoxine-dependent seizures can be due to genetic (autosomal recessive) pyridoxine dependency, or more commonly, a result of the use of high-dose pyridoxine during pregnancy (8197,8198).
• Sideroblastic anemia. Oral vitamin B6 is effective for treating hereditary sideroblastic anemia. Details: Taking vitamin B6 (pyridoxine) orally is effective for treating hereditary sideroblastic anemia (15,9518). Taking the active form of vitamin B6 (pyridoxal-5'-phosphate) also seems to be effective in cases in which the patient does not respond to pyridoxine (93049).
• Vitamin B6 deficiency. Oral vitamin B6 is effective for preventing and treating vitamin B6 deficiency. Details: Taking oral vitamin B6 can prevent and treat vitamin B6 deficiency (15).

LIKELY EFFECTIVE

• Hyperhomocysteinemia. Taking vitamin B6 orally, alone or in combination with folic acid, is effective for reducing hyperhomocysteinemia. Details: Vitamin B6 (pyridoxine) seems to lower homocysteine concentrations when folic acid and vitamin B12 are at physiologic levels or when given with folic acid and vitamin B12 supplements (9451,83042,107136). A combination of vitamin B6 100 mg and folic acid 0.5 mg daily seems to lower homocysteine levels by about 35% and is recommended for people with postprandial hyperhomocysteinemia (1489,9406). Other research shows that taking pyridoxine 50-200 mg daily reduces postprandial homocysteine levels by 32% to 35% (9406,10350). Pyridoxine also seems to reduce homocysteine levels in patients with kidney failure, kidney transplant patients (1489,6884,9414,9415), or patients who receive general anesthesia with nitrous oxide (9481). However, some research in healthy adults suggests that adding pyridoxine to folic acid might not provide any additional benefit over folic acid alone (9400,9405,9409,50145). Hyperhomocysteinemia is considered by some to be an independent risk factor for atherosclerosis, recurrent thromboembolism, deep vein thrombosis, myocardial infarction, and ischemic stroke (1899,3323,9402,9405,9408,9409). However, elevated homocysteine levels may be a marker, as opposed to a cause, of vascular disease (11387,11388). A 5 µmol/L increase in plasma homocysteine increases the risk of cerebrovascular disease by 50% and the odds of coronary heart disease by 60% and 80% in males and females, respectively (9407,9411). However, it is not clear if reducing homocysteine levels results in reduced cardiovascular morbidity and mortality (1489,6883,6884,9308,9400,9405,9409). Folic acid, vitamin B6, and vitamin B12 supplementation can reduce total homocysteine from 13.4 to 11 µmol/L. However, this reduction does not seem to help with secondary prevention of death or myocardial infarction, and some research even suggests an increase in cardiovascular disease (CVD) risk (11387,13482,50423,83050,97619). There is also debate about whether supplementation with homocysteine-lowering B vitamins can reduce the risk of stroke. A number of large clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with CVD or impaired renal function (11387,13482,50423,83050,96150). However, a more recent meta-analysis shows that B vitamin supplementation modestly reduces the relative risk of stroke by 10% when compared with placebo in patients at risk for or with a history of CVD (97619). Also, a meta-analysis in patients with a history of stroke shows that B vitamin supplementation modestly reduces the relative risk of stroke recurrence by 13% and the risk of vascular death by 11% when compared with placebo (107136).

POSSIBLY EFFECTIVE

• Antipsychotic-induced hyperprolactinemia. It is unclear if oral vitamin B6 is beneficial for patients with antipsychotic-induced hyperprolactinemia. Details: Clinical research in male patients with hyperprolactinemia who are on a consistent antipsychotic dose shows that taking vitamin B6 300 mg twice daily for 16 weeks reduces serum prolactin levels by 68%, compared with 37% in patients taking aripiprazole 5 mg twice daily. Also, 67% of patients taking vitamin B6 had prolactin levels less than 40 mcg/mL versus 2% of those taking aripiprazole (107128).
• Kidney stones (nephrolithiasis). Oral vitamin B6 seems to decrease urinary oxalate levels and decrease the risk of kidney stone formation in some patients. Details: There is some evidence that taking vitamin B6 (pyridoxine) orally, alone or in combination with magnesium, can decrease urinary oxalate levels in people with type I primary hyperoxaluria, a hereditary disorder (1201,6437,6438,6439,6440,8548,8549,8550). Additionally, a small clinical study in this population suggests that intravenous pyridoxine hydrochloride can reduce urinary oxalate by 25.5% when compared to baseline (90796). In patients with idiopathic hyperoxaluria, taking a combination of pyridoxine 25mg and magnesium oxide 400 mg for 3 months decreases urinary oxalate by approximately 16%, with 68% of patients experiencing a reduction. However, supplementation is less effective than following a low-oxalate diet, which reduces urinary oxalate in 91% of patients by an average of 31% (107127). There is also preliminary evidence that higher pyridoxine intake in females with no history of kidney stones is associated with decreased risk of kidney stone formation (6441), but this association has not been found in males (6442).
• Pregnancy-induced nausea and vomiting. Oral vitamin B6 may reduce nausea and vomiting in some pregnant patients and is sometimes used in combination with doxylamine. Details: While some conflicting evidence exists, most small clinical studies suggest that oral vitamin B6 is effective for improving nausea and vomiting associated with pregnancy when compared with baseline or placebo. However, vitamin B6 may not be as effective as ginger (110459). Two small clinical studies show that taking vitamin B6 (pyridoxine) 25 mg every 8 hours for 3-4 days decreases pregnancy-induced nausea severity and vomiting incidence when compared with placebo (6168,16306). A larger clinical trial shows that taking lower doses of vitamin B6, 10 mg every 8 hours over 5 days, improves pregnancy-induced nausea, but not vomiting, when compared with placebo (6167). A small clinical study in patients with mild to moderate nausea and vomiting shows that taking a higher dose of 40 mg twice daily for 4 days is more effective than placebo, but no better than ginger 500 mg twice daily (99404). The American College of Obstetrics and Gynecology (ACOG) considers vitamin B6 at a dose of 10-25 mg 3 to 4 times daily a first-line treatment for pregnancy-induced nausea and vomiting due to its benign safety profile (111601). However, it is not effective for all patients, such as those with hyperemesis gravidarum, a severe form of pregnancy-induced nausea and vomiting. Adding vitamin B6 20 mg three times daily for 2 weeks to intravenous rehydration, metoclopramide, and thiamine seems to be no more effective than placebo for reducing vomiting in hyperemesis gravidarum (99405). Vitamin B6 is also sometimes used in combination with doxylamine. In fact, a combination of vitamin B6 plus doxylamine (Diclegis or Bonjesta, Duchesnay Inc., and various generics) has been approved by the US Food and Drug Administration (FDA) as a prescription product111601). ACOG recommends vitamin B6 in combination with doxylamine as another first-line treatment option (111601). However, the clinical trial used to obtain FDA approval has some methodological problems, and the significance of the results has been questioned. The improvement in symptom scores seen with Diclegis was less than one point on a 13-point scale, which is unlikely to be clinically significant (97998). Also, some clinical research shows that taking pyridoxine 25 mg and doxylamine 12.5 mg is less effective than ondansetron 4 mg when taken every 8 hours for 5 days. Only 41% of the patients using pyridoxine and doxylamine had a clinically significant reduction in nausea, compared to 92% of patients using ondansetron (90797). The combination of vitamin B6 and doxylamine is also studied with acupuncture. A large clinical study in patients with moderate to severe pregnancy-induced nausea and vomiting conducted in China shows that taking vitamin B6-doxylamine (Diclegis, Duchesnay, Inc) 20 to 40 mg each at bedtime for 14 days in combination with daily acupuncture modestly improves patient-reported nausea and vomiting scores when compared with either intervention alone (111820). However, it is unclear whether this improvement is clinically significant.
• Premenstrual syndrome (PMS). Oral vitamin B6 seems to reduce PMS symptoms. Details: There is some evidence that taking vitamin B6 (pyridoxine) orally can improve symptoms of PMS such as breast pain or tenderness (mastalgia) and depression in some patients. Pyridoxine in doses of at least 50 mg daily, plus magnesium oxide 200 mg daily, seems to relieve PMS-related anxiety and other symptoms (8555,39007,82962). Although some clinicians advocate doses of pyridoxine 200-500 mg daily for PMS, doses of 50-100 mg daily seem to work just as well. There is no apparent dose-response curve for PMS, so the lowest effective dose should be used. Higher doses might increase the risk of side effects (3093).

POSSIBLY INEFFECTIVE

• Age-related cognitive decline. Oral vitamin B6 does not seem to slow age-related cognitive decline. Details: One clinical trial in elderly people with memory complaints shows that taking a combination of B vitamins, including folic acid 0.8 mg, vitamin B12 0.5 mg, and vitamin B6 (form not specified) 20 mg daily for 24 months reduces cerebral atrophy in the gray matter regions associated with Alzheimer disease by up to seven-fold when compared with placebo. However, this protection does not occur in patients with the lowest average blood levels of homocysteine (90374). Furthermore, other clinical research shows that taking vitamin B6 (pyridoxine) 3-75 mg daily in combination with folic acid and vitamin B12 does not improve cognitive function in elderly adults (14392,50225,50510).
• Alzheimer disease. Oral vitamin B6 does not seem to improve cognitive function in patients with Alzheimer disease when used in combination with other B vitamins. Also, oral vitamin B6 does not seem to reduce the risk of developing this condition. Details: Clinical research in patients with probable Alzheimer disease taking routine medications shows that taking vitamin B6 25 mg with folic acid 5 mg and vitamin B12 1 mg daily for 18 months does not have a beneficial effect on cognitive function or the severity of disease when compared with placebo. In this study, all patients were consuming a folate-fortified diet (50319). Also, population research in elderly adults has found that a high intake of vitamin B6 from dietary or supplemental sources is not associated with a decreased risk of Alzheimer disease when compared to lower vitamin B6 intake (13165,15270).
• Carpal tunnel syndrome. Oral vitamin B6 does not seem to reduce symptoms of carpal tunnel syndrome. Details: Most research shows that people with carpal tunnel syndrome are not generally deficient in vitamin B6 and do not benefit from taking vitamin B6 supplements (8203,8937,9448,9450,9478,9482). Although early studies by a single group of researchers, as well as anecdotal reports, suggest that taking vitamin B6 may relieve carpal tunnel symptoms, more reliable research has not supported these findings (8202,9445,9447,9449,9483,15955,83086). Vitamin B6 has also been evaluated in combination with other ingredients. A moderate-sized clinical study in adults with mild to moderate carpal tunnel syndrome shows that taking a combination product containing vitamin B6, alpha-lipoic acid, acetyl-L-carnitine, phosphatidylserine, turmeric, and vitamins C, E, B1, B2, and B12 twice daily for 60 days reduces symptom severity and pain but does not improve measures of hand and wrist function when compared with a control (111702). The dose of vitamin B6 was not provided. The validity of this study is limited by the lack of blinding and placebo. Additionally, it is unclear if the effects are due to vitamin B6, other ingredients, or the combination.
• Cataracts. Oral vitamin B6 does not seem to slow cataract development. Details: Clinical research in females with existing cardiovascular disease (CVD) or at increased risk of CVD shows that taking a combination of folic acid 2.5 mg, vitamin B6 (form not specified) 50 mg, and vitamin B12 1 mg daily for an average of 7.3 years does not reduce the risk of cataracts when compared with placebo. Furthermore, the risk of cataract extraction was increased by 28% (96149).
• Chemotherapy-induced acral erythema. While some conflicting evidence exists, most research suggests that oral or topical vitamin B6 does not seem to prevent or reduce the severity of acral erythema induced by chemotherapy. Details: A meta-analysis of 10 clinical trials and 4 observational studies shows that taking vitamin B6 60-500 mg daily for up to 8 chemotherapy cycles does not prevent chemotherapy-induced acral erythema or reduce the incidence of severe cases when compared with control. Most studies used capecitabine chemotherapy alone or in combination, and one study used pegylated liposomal doxorubicin; however, no subgroup analysis was conducted to differentiate chemotherapy regimens. Results did not seem to vary based on study location, study design, or vitamin B6 dose (104930). However, a more recent preliminary clinical study in patients receiving doxorubicin for multiple myeloma shows that taking vitamin B6 100 mg on the first day of chemotherapy then twice daily for 7 days with each cycle reduces the risk of developing acral erythema by 72%, but does not improve the severity of acral erythema, when compared with no vitamin B6 supplementation (110458). Also, one small, low-quality clinical study suggests that taking vitamin B6 400 mg daily reduces the risk of moderate or severe chemotherapy-induced acral erythema when compared with vitamin B6 200 mg daily; however, the higher dose also seems to be associated with worsened tumor response and increased treatment failure (97620). Topical vitamin B6 has also failed to show benefit. A small clinical study in patients with acral erythema from capecitabine or pegylated liposomal doxorubicin shows that applying vitamin B6 1% cream to affected areas three times daily for 6 weeks does not improve symptoms when compared with placebo (104929).
• Colorectal adenoma. Oral vitamin B6 does not seem to reduce the risk of developing colorectal adenomas. Details: Clinical research shows that taking a combination of B vitamins, including folic acid 2.5 mg, vitamin B6 (pyridoxine) 50 mg, and vitamin B12 1 mg, daily for up to 9.2 years does not reduce the risk of colorectal adenoma in females at high risk of cardiovascular disease when compared with placebo (90389).
• Eclampsia. Oral or intramuscular vitamin B6 does not seem to reduce the risk of eclampsia. Details: Meta-analyses of limited clinical research in pregnant patients show that taking vitamin B6 (pyridoxine), either as 25 mg daily or a single dose of 100 mg orally or intramuscularly, does not reduce the risk of eclampsia when compared with control (83046,96166).
• Osteoporosis. Oral vitamin B6 does not seem to reduce the risk of osteoporotic fractures. Details: Clinical research in patients with cerebrovascular disease shows that taking a combination of B vitamins, including folic acid 2 mg, vitamin B6 (form not specified) 25 mg, and vitamin B12 500 mcg daily for up to 10.5 years does not prevent osteoporotic fractures when compared with placebo (90377). Furthermore, a secondary analysis of two large studies in patients with cardiovascular disease has found that taking vitamin B6 (pyridoxine) 40 mg daily in addition to folic acid and vitamin B12 for 1-3 years is associated with a 42% increased risk of hip fracture over an 11-year period when compared with only folic acid and vitamin B12 (96163). This finding is limited because these studies were not designed to assess the effects of vitamin B6 on fracture risk and the analyses were not adjusted for baseline bone health or fall risk.
• Pre-eclampsia. Oral or intramuscular vitamin B6 does not seem to reduce the risk of pre-eclampsia. Details: Meta-analyses of limited clinical research in pregnant patients show that taking vitamin B6 (pyridoxine), either as 25 mg daily or a single dose of 100 mg orally or intramuscularly, does not reduce the risk of pre-eclampsia when compared with placebo (83046,96166).
• Preterm labor. Oral or intramuscular vitamin B6 does not seem to reduce the risk of preterm labor. Details: Meta-analyses of limited clinical research in pregnant patients shows that taking vitamin B6 (pyridoxine), either as 25 mg daily or a single dose of 100 mg orally or intramuscularly, does not reduce the risk of preterm labor when compared with placebo (83046,96166).